DBU-mediated regioselective intramolecular cyclization/dehydration of ortho diketo phenoxyethers: A synthesis of 2,3-substituted γ-benzopyranones

Article abstract of DOI:10.1016/j.tet.2013.07.104

The regioselective cyclization/dehydration sequence of ortho diketo phenoxyethers induced by DBU has been explored. The results demonstrated a high degree of selectivity with preference for 6-exo-trig cyclization leading to the formation of γ-benzopyranone derivatives in good yield.

Full text of DOI:10.1016/j.tet.2013.07.104

Tetrahedron 69 (2013) 9335e9348
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
DBU-mediated regioselective intramolecular cyclization/
dehydration of ortho diketo phenoxyethers: a synthesis
of 2,3-substituted
g
-benzopyranones
,
a,b
Sofia Bensulong b, Jutatip Boonsombat a , Somsak Ruchirawat
*
a Chulabhorn Research Institute, 54 Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand
b Program on Chemical Biology, Chulabhorn Graduate Institute, Center of Excellence on Environmental Health and Toxicology, CHE, Ministry of
Education, 54 Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand
a r t i c l e i n f o
a b s t r a c t
Article history:
The regioselective cyclization/dehydration sequence of ortho diketo phenoxyethers induced by DBU has
been explored. The results demonstrated a high degree of selectivity with preference for 6-exo-trig cy-
Received 10 March 2013
Received in revised form 8 July 2013
Accepted 22 July 2013
clization leading to the formation of
g
-benzopyranone derivatives in good yield.
Ó 2013 Elsevier Ltd. All rights reserved.
Available online 4 August 2013
Keywords:
Regioselective cyclization
Benzopyran
Benzofuran
Benzopyranone
Isoflavone
1. Introduction
yield, the substituents on the ensuing heterocyclic rings weremostly
simple aryl or alkyl group thus greatly limiting further functionali-
zation to a more complex skeleton.4
Benzofuran and benzopyran scaffolds are widely distributed in
many naturally occurring compounds, and show a wide range of
biological activities, for instance, insecticidal, analgesic, antibacte-
rial, anticancer, anti-HIV, antimicrobial, and antioxidant properties.1
Additionally, they constitute versatile building blocks for entry into
more complex molecules of biological interest.2 Owing to their bi-
ologically and structurally interesting properties, various synthetic
routes toward benzofuran and benzopyran derivatives have been
developed over the years.3 Among them, the attachment of the
furanyl or pyranyl portion, formed by intramolecular cyclization,
onto the existing benzenoid rings is probably one of the most direct
and potentially versatile routes to assemble these ring systems.3e11
This cyclization requires ortho substituted phenol or phenoxy de-
rivatives as precursors and the reaction can proceed either through
carboneoxygen bond formation or carbonecarbon bond formation
in the key step. In an intramolecular carboneoxygen bond annula-
tion, the oxygen in the common phenol derivatives was used as
a nucleophile to attack electrophilic substituents.4 Although the
corresponding benzofurans or benzopyrans were obtained in good
The intramolecular carbonecarbon bond formation to construct
these heterocycles is an alternative route, which holds potential
synthetic utility in expanding the scope of functional group vari-
ability onto benzofurans or benzopyrans (Scheme 1).5e11
O
R2
HO
OH
R2
R2
R1
n
a)
R1
or
O
n= 0,1
O
n = 1
R1
O
n = 0
R2
R2
R1
R1
O
b)
R2
R1
O
O
Scheme 1. Intramolecular carbonecarbon bond cyclization of ortho substituted phenyl
ether.
In this mode of cyclization, the methylene group on the phenox-
yether was used to cyclize onto the ortho electrophilic substituent,
including a carbonyl group, alkene, and alkyne. Among these, the
annulation reaction involving a carbonyl functionality as electrophile
* Corresponding author. Tel./fax: þ66 2 553 8555x8803/8982; e-mail addresses:
jutatip@cri.or.th, Jutatip_b@yahoo.com (J. Boonsombat).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.07.104

9336
S. Bensulong et al. / Tetrahedron 69 (2013) 9335e9348
was the most typical route to construct these two heterocycles
(Scheme 1a). Different ring sizes could be obtained by placing the
carbonyl group into a suitable position, and promotion of cyclization
was effectively done by generation of a carbanion using bases,5 or
a radical by photochemical hydrogen atom abstraction.6 Even though,
this route provided efficient and reliable formation of the requisite
benzofurans or benzopyrans, the precise position of the carbonyl
group on the substrate can make synthesis difficult in practice. On the
other hand, regioselective formation by using an alkene and alkyne as
electrophiles demonstrated the simplicity and expediency of prepa-
ration of precursors because the specific nucleophilic site is not vital
(Scheme 1b). While in such cases regiochemical selectivity between
five-membered and six-membered cyclization processes could occur
leading to different ring sizes, numerous examples demonstrated
excellent regioselectivity in product formation depending on sub-
strates and conditions. Liang demonstrated the exclusive formation of
2-aroyl-3-vinyl-benzofuran by way of utilizing palladium catalyzed
cyclization/isomerization of a propargylic arene.7 Terada reported
phosphazene base-catalyzed intramolecular carbonecarbon bond
cyclization with highly selective formation of 2-substituted 3-
benzylbenzofurans from ortho alkynyl phenylethers.8 Recently,
Wang nicely expanded the intramolecular carbonecarbon bond for-
mation to an alkene or alkyne of an ortho phenoxyether by intra-
molecular nucleophilic attack of the carbanion generated by t-BuOK.9
Remarkably, the cyclized products could be formed in high regiose-
lectivity depending on alkene or alkyne used. When alkenes were
used, the 6-endo-trig cyclization was formed to give the benzopyr-
ans.9b Incontrast, whenalkyneswereused, 5-exo-digpathwaytoyield
the benzofurans was exclusively observed.9a
2. Results and discussion
2.1. Preparation of diketo precursors
We began our investigation by preparing the desired diketo
precursor 1, which could be accomplished in three steps from
halophenols 4aeg (Scheme 3).
Despite the fact that the regioselective cyclization simplifies the
substrate formation and the carbonyl group offers high proficiency
as an electrophilic site for benzofuran or benzopyran construction,
the intramolecular carbonecarbon bond formation using related
ortho dicarbonyl precursors has not been the subject of a detailed
study to date. There have been scarce examples on the use of ortho
dicarbonyl phenylethers with limited substituents in the synthesis
of these heterocycles. Ruchirawat reported the synthesis of 2-
Scheme 3. Preparation of dione phenoxyethers.
Firstly, the phenols 4aef were deprotonated with K2CO3 and
then alkylated with ethyl 2-bromoacetate to furnish the phenox-
yacetates 5aef in excellent yield (82e99%). Ethyl 2-(2-iodo-5-
(tosyloxy)phenoxy)acetate 5g was, in turn, prepared in a consec-
utive manner from 4g by treatment with TsCl and K2CO3 in
refluxing acetone overnight and further refluxing with ethyl 2-
bromoacetate (5) for an additional 3 h. Afterward, the phenox-
yacetates 5aeg were subjected to Sonogashira cross coupling re-
action with a variety of terminal alkynes (7) in the presence of CuI,
Pd(PPh3)4, and Et3N in MeCN providing alkynyl phenoxyethers
6aeu in good to excellent yield (44e100%). The third step in the
synthesis involved the oxidation of the alkyne moiety to dicar-
bonyls. In this regard, the alkynyl phenoxyether 6a was used for
investigating oxidation reaction conditions.13 The Wacker type
oxidation, in which molecular oxygen as the stoichiometric sole
oxidant and catalytic PdBr2 and CuBr2 were used,14 could produce
arylbenzofurans via the in situ formation of aryl a-keto esters from
the rearrangement of an aromatic cyanohydrin carbonate ester in-
duced by LDA.10 Roengsamran, in the synthesis of dehydrorotenoids,
reported the generation of benzopyranones by treatment of an aryl
diketone intermediate with aqueous sulfuric acid.11 The limited
substituent patterns and insufficient data of the carbonecarbon
bond cyclization to dicarbonyl systems in the formation of benzo-
furans or benzopyrans prompted us to investigate the effect of dif-
ferent substituents on their regioselectivity. We focused our workon
the utilization of the carbonecarbon bond formation by the base
induced intramolecular cyclization reaction of an ortho diketo
phenoxyether tethered with a carboxylic ester (i.e., 1). The use of
a carboxylic ester not only serves as an activating group for the
generation of a carbanion, but its functionality could also be easily
manipulated for further synthesis. In this study, we found that the
intramolecular cyclization induced by DBU demonstrated a high
degree of regioselectivity toward the 6-exo-trig cyclization with
concomitant extrusion of H2O, thus providing a two-step sequence
of intramolecular carbonecarbon bond cyclization/dehydration to
15
product 1a in 58%. The RuO2/NaIO4 system was able to produce
1a in moderate yield (40%), but a better result could be obtained
11
by RuCl3/NaIO4 in the presence of NaHCO3/MgSO4 providing the
corresponding product in excellent yield (96%) within 1 h. The
increase in yield is presumably the result of the buffered reaction
conditions.16 With this latter reaction condition, the conversion of
various substituted alkynes 6aer to the corresponding diketo
phenoxyethers 1aer was completed within 1e3 h in good to ex-
cellent yield (65e95% yield). However, oxidation of compound 6s
led to an unidentified complex mixture, presumably due to the
instability of the substrate. In addition, with alkynyl phenox-
yethers 6t and 6u, containing the TMS and H terminus, the re-
actions produced the 2-(2-ethoxy-2-oxoethoxy) benzoic acid 8 as
the only product isolated by column chromatography in 74% and
88%, respectively.17 The ensuing diketones 1t and 1u probably
underwent photolysis resulting in the oxidative carbonecarbon
bond cleavage to give the carboxylic acid 8.13e
2,3-substituted g
-benzopyranone 212 in one-pot (Scheme 2).
Scheme 2. Regioselective intramolecular cyclization/dehydration of ortho diketo
phenoxyether using DBU.

S. Bensulong et al. / Tetrahedron 69 (2013) 9335e9348
9337
2.2. Investigation of base induced cyclization reaction
conversion within 3 h to provide the corresponding cyclization/de-
hydration products. The regioselectivity toward 6-exo-trig cyclized
product 2a could be observed in 57% yield together with a small
amount of 5-exo-trig cyclized product 3a in 3% (entry 9).
When commencing the investigation, we first explored the
intramolecular carbonecarbon bond cyclization/dehydration se-
quence with compound 1a as a model substrate. Thus, the cycli-
zation of diketo phenoxyether 1a would lead to 3-carbonylated
benzofuran-2-carboxylate ester 2a via 5-exo-trig cyclization or 3-
substituted benzopyranone-2-carboxylate ester 3a via 6-exo-trig
cyclization. We initially examined the reaction of 1a in a variety of
basic conditions. As can be seen in Table 1 in all cases where the
reaction occurred, the 6-exo cyclization product was predominant.
When the substrate 1awas subjected to DMAP in DMF, cyclization
did not occur at all even at 100 ꢀC (entry 1). The use of phosphazene
base P4-t-Bu gave no reaction in refluxing toluene or decomposition
in DMSO at 100 ꢀC (entries 2 and 3). When the substrate 1a reacted
with NaOEt in EtOH at room temperature, only recovered starting
material was found (entry 4); however, when the reactionwas heated
at reflux, the reaction could not proceed to completion, but three
different cyclized products were formed along with 35% of the re-
covered starting material (entry 5). This condition could induce cy-
clization followed by dehydration to give rise to benzopyranone 2a
(14%), benzofuran 3a (7%), and 6-exo cyclized alcohol II (11% yield).
The preference for the 6-exo-trig pathway was also observed when
heating 1a with NaH in refluxing toluene in which the 6-exo cyclized
alcohol II was obtained in 18% yield together with benzopyranone 2a
(4%), benzofuran 3a (9%), and the recovered starting material (44%)
(entry 6). Using t-BuOK in THF (entry 7), which was effectively
employed in similar systems,9 did not work well with our substrate.
Only 9% of benzopyranone product 2a was accompanied by major
decomposition. When 1awas treated with K2CO3 in DMFat 100 ꢀC for
24 h, intramolecular carbonecarbon bond cyclization occurred with
complete loss of H2O to deliver 2a and 3b in 36% and 4%, respectively
(entry 8). The low combined yield of products could be due to the
long reaction time at high temperature to achieve the full conversion.
Gratifyingly, the use of DBU in DMF at 100 ꢀC gave complete
We next continued to investigate the regioselectivity of the DBU
mediated cyclization/dehydration sequence with respect to sol-
vents (entries 9e13). By switching to non-polar solvent toluene, the
reaction required a long reaction time to complete, and the regio-
selectivity toward a 6-exo-trig cyclized product was drastically di-
minished to give only 41% of 2a along with 24% of 3a (entry 10). By
contrast, in polar solvents, the reactions were complete in much
shorter time, within 3 h in DMF and MeCN, 8 h in EtOH, and 1 h in
DMSO (entries 9e13). Moreover, the regioselectivity of the reaction
in polar solvents also displayed higher selectivity toward a 6-exo-
trig cyclized product 2a than that of in toluene.19 Furthermore,
when comparing polar solvents, DMSO showed excellent selectiv-
ity giving a 6-exo-trig cyclized product 2a in 84% yield with a barely
detectable amount of 5-exo-trig cyclized product 3a (3%) (entries 9,
11e13). We also examined the effect of DBU in DMSO at room
temperature (entry 14) as well as catalytic DBU (entry 15). In both
cases, the reactions proceeded with concomitant loss of H2O, but
reaction times were exceedingly long. A significant amount of
starting material could be isolated after 3 days, thus making these
conditions (entries 14 and 15) impractical for synthesis.
A plausible mechanism is described in Scheme 4. The present
molecular cyclization was most probably initiated by the generation
of a carbanion intermediate via deprotonation of the most acidic
proton by base. Carbanion I thus formed then underwent nucleo-
philic attack to the
b-carbonyl through intramolecular 6-exo-trig
cyclization, followed by dehydration to yield benzopyranone de-
rivative 2a. The dehydrationwas presumably driven by the formation
of the more conjugated
regioisomer 3a, conversely, derived from the cyclization of carbanion
to the -carbonyl through intramolecular 5-exo-trig pathway.
a,b unsaturated keto ester. The benzofuran
a
Table 1
Investigation of the cyclization of 1a under various basic conditions
Entry
Reagents
Solvent
T (ꢀC)
Timea
Yieldb (%)
Yieldb (%)
2a
3a
1
2
3
4
5
6
7
8
DMAP
P4-t-Bu
P4-t-Bu
NaOEt
NaOEt
NaH
t-BuOK
K2CO3
DBU
DBU
DBU
DBU
DBU
DMF
100
100
24 h
4 h
No Rx
Complex mixture
No Rx
DMSO
Toluene
EtOH
EtOH
Toluene
THF
Scheme 4. Proposed mechanism for an intramolecular carbonecarbon bond cycliza-
tion/dehydration reaction.
Reflux
rt
Reflux
Reflux
Reflux
100
24 h
24 h
24 hc
24 hc
20 h
24 h
3 h
24 h
3 h
8 h
No Rx
14d
4e
7
9
d
9
2.3. Exploring substrate variation
DMF
DMF
36
57
41
45
30
84
23
48
4
4
24
13
8
3
3
2
9
100
After finding the optimal reaction condition (DBU, DMSO,
100 ꢀC) for the cyclization of 1a, we further examined the scope and
limitation of the DBU induced 6-exo-trig cyclization with a series of
ortho diketo phenoxyether derivatives. We found that the intra-
molecular cyclization/dehydration sequence induced by DBU
demonstrated a high degree of regioselectivity. In most cases, the
corresponding cyclization/dehydration adducts were formed fa-
voring benzopyranone 2 in good yield; nonetheless, the influence
of the steric and electronic effect to the cyclization mode could
apparently be recognized as shown in Table 2.
10
11
12
13
14
15
Toluene
MeCN
EtOH
DMSO
DMSO
DMSO
Reflux
Reflux
Reflux
100
rt
100
1 h
DBU
0.25
3 daysc
3 daysc
equiv DBU
a
Determined by monitoring the consumption of stating material by TLC.
Isolated yield.
b
c
The reaction was not completed.
Along with 11% of alcohol II18 and 35% of recovered starting
d
The simple phenoxyether containing alkyl or simple phenyl
substituents on the
the regioselective formation of benzopyranones with the exception
of entry 13 (R¼t-Bu). The introduction of a t-Bu group at the
carbonyl induced the opposite regioselectivity, giving rise to
b-carbonyl (entries 1e3, and entry 13) provided
material.
b
-
e
Along with 18% of alcohol II and 44% of recovered starting material.

9338
S. Bensulong et al. / Tetrahedron 69 (2013) 9335e9348
Table 2
formed. Thus, this result could be inferred to the contribution of res-
onance effect from ortho phenoxyether tether.
The resonance effect of substituents in the meta and para posi-
tions were also investigated. The additional OMe group in the meta
Intramolecular cyclization/dehydration reaction of various ortho diketo phenox-
yether 1 with DBU
position on the b-carbonyl substituent exhibited a slight influence on
product selectivity as seen in entries 11 and 12. The m,p-(OMe)2eAr
group gave 53% of benzopyranone 1k with 16% of benzofuran 3k,
whereas the p-OMeeAr group provided 57% of benzopyranone 1j
with 13% of benzofuran 3j.
Entry
1
R1
R2
R3
R
Time 2, Yielda 3, Yielda
(h)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n OMe
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OMe
H
H
H
H
H
H
H
H
H
H
H
H
H
OMe
OMe
H
OTs
OTs
H
Ph
n-Bu
CH2OTHP
Ph
p-OMeeAr
n-Bu
1
1
2
1
1
1
1
1
3
1
1
1
4
84%
74%
73%
78%
70%
73%
56%
56%
61%
57%
53%
54%
d
3%
d
Surprisingly, the placement of an OMe group in the ortho position of
both phenoxyether and phenyl rings on the
ing results to our expectation (entries 9 and 14). When the o-OMeeAr
group wasplaced at the -carbonyl (entry 9), the benzopyranone 2iwas
b-carbonyl gave contrast-
d
d
b
d
d
received exclusively without contamination of the expected benzofu-
ran 3i, which should theoretically be formed as the result of the
weakening electrophilicity of the b-carbonyl by an ortho donating
resonance effect. These results could be explained by the concept of
steric inhibition of the resonance effect.20 The introduction of the OMe
group at the ortho position contributed to the steric hindrance, and
Ph
d
m,p-(OMe)2eAr
o-OMeeAr
p-OMeeAr
m,p-(OMe)2eAr
d
9
d
10
11
12
13
14
15
16
H
H
13%
16%
12%b
42%
64%
d
CO2Et Ph
H
OMe
H
OMe
t-Bu
m,p-(OMe)2eAr
p-NO2eAr
blocked the attainment of coplanarity between the
and the phenyl ring. As a consequent, resonance from the o-OMeeAr
group to the -carbonyl was inhibited and made the -carbonyl more
b-carbonyl group
2
d
1o
1p
H
H
3c
1c
d
b
b
p-NO2eAr
d
d
resemble an isolated carbonyl, which was more susceptible toward the
generated carbanion, resulting in the preference for 6-exo formation.
The same rationalization could be applied for the formation of 5-exo
a
Isolated yield.
Along with the formation of 9 in 14% yield.
Complex mixture was obtained.
b
c
benzofuran 3n. The OMe group at R1 on the phenoxyether forced the
a-
carbonyl away from the plane of the aromatic ring inhibiting the effect
of resonance from the phenoxyether, while the -carbonyl, which had
no ortho substituent feasibly gained resonance effect from the m,p-
(OMe)2eAr substituent. As a result, the -carbonyl was more electro-
benzofuran 3m. The steric bulkiness of the t-Bu substituent most
probably hindered the attack of the carbanion at the -carbonyl and
directed the attack to the less hindered -carbonyl. The longer re-
b
b
a
a
action time required for completion of 3m (4 h) inferred the diffi-
culty in product formation compared to the shorter reactions used
in 6-exo-trig formation.
philic, thus giving benzofuran 3n as sole product.
We also examined the effect of the strong electron withdrawing
NO2 substituent on both phenoxyether and phenyl rings on the b-
When placing a variety of substituents on both the phenox-
yether and phenyl rings on the b-carbonyl, the reactions yielded
carbonyl. Of many reports, examples were mostly illustrated with
moderate electron-withdrawing groups while the nitro substituted
substrates were scarcely examined.3e11 Hence it drew us to explore
the effect of such a strong group toward the cyclization. The in-
benzopyranones 2 without detectable amounts of benzofurans 3 on
both TLC and 1H NMR of crude product (entries 2e9). The meta
substituent on the phenoxyether also has no obvious influence on
the regioselectivity toward cyclization as demonstrated by phe-
noxyethers 1b and 1f in which benzopyranones 2b and 2f were
exclusively formed in comparable product yield (entries 2 and 6).
The influence of electronic effects toward cyclization was
detected when the substrate contained an electron-donating
troduction of NO2 functionality on phenyl ring located on the b-
carbonyl (R group) (entries 15 and 16, Table 2) resulted in de-
composition as observed by both TLC and 1H NMR spectroscopy of
the crude product. These results could be attributed to the in-
stability under base at high temperature of these nitro com-
pounds.4a Interestingly, when placing the NO2 group on R3, the
reaction exclusively provided 5-exo-trig benzofuran 10 (Scheme 5).
group, p-OMeeAr at the b-carbonyl. When substrate 1j was sub-
jected to the DBU-cyclization condition, besides the major product
benzopyranone 2j in 57% yield, a minor amount of benzofuran 3j
(13%) was also obtained. This outcome could be ascribed by the
electron donating nature through the resonance effect of the para
OMe group decreasing the electrophilicity of the b-carbonyl thus
attenuating the regioselectivity toward 6-exo-trig cyclization. Along
the same line, in the presence of electron withdrawing CO2Et on R3,
the cyclization resulted in 54% of benzopyranone 1l together with
12% of benzofuran 3l. In this circumstance, the electron with-
drawing property of CO2Et in turn enhanced the electrophilicity of
Scheme 5. The generation of nitro benzofuran 10 from 1q and 1r.
These results indicated that the very strong electron withdrawing
nature of the NO2 group greatly enhanced the electrophilic nature
a
-carbonyl thus leading to the competitive formation of 5-exo-trig
to give benzofuran 3l.
of the a-carbonyl and overrode the donating effect of the ortho
On the basis of our results, it seemed that the ortho phenoxyether
tether on substrates 1 played a significant role in the product selec-
tivity by donating an electron through resonance effect thus weak-
ether tethering. Further, the absence of the keto side chain on the C-
3 position on the NO2 substituted benzofuran 10 could be the result
of a strong electron withdrawing property of the nitro group as
ascribed in the next scheme (Scheme 6).
ening the electrophilicity of the a-carbonyl. As a consequence, the
mode of cyclization then was directed to 6-exo-trig cyclization to give
benzopyranones 2. Such effect of the ortho phenoxyether was sup-
The interpretation of the reaction mechanism for the formation
of 10 could be rationally illustrated as follows (Scheme 6). Initially,
ported by the use of substrate 1e bearing a p-OMeeAr on both
b-
the carbonecarbon bond formation of carbanion IV to a-carbonyl by
carbonyl (R group) and a para-substituent on phenoxyether (entry 5,
Table 2). In thiscase, eachOMe groupcould equally donate anelectron
to its adjacent carbonyl, butonly the6-exo-trig benzopyranone2ewas
5-exo-trig cyclization gave rise to the formation of alkoxide V, which
could further react with the adjacent carbonyl to provide the alkoxy
epoxide intermediate VI. The ring opening of the epoxide led to the

S. Bensulong et al. / Tetrahedron 69 (2013) 9335e9348
9339
For compound 3n, which had no H at R1, the structure of ben-
zofuran was inferred from the carbonyl ketone at 189.7 ppm, hence
resembling the isolated ketone as found in benzofuran structure 3.
Further rationalization was made from a strong HMBC correlation
between the 20 and 60 protons and the carbonyl ketone confirming
the structure of benzofuran 3n.
3. Conclusion
In conclusion, the regioselective intramolecular cyclization/de-
hydration sequence of ortho diketo pheoxyethers to afford benzo-
pyranones, specifically g-benzopyranones, has been developed. This
method has illustrated a practical protocol starting from iodo or
bromo phenol derivatives through a sequence of Sonogashira cross
coupling, oxidation of alkyne to dione and DBU-induced cyclization.
The 6-exo-trig pathway was exclusive or dominant in most sub-
strates except the substrate containing a strong electron with-
drawing NO2 group at R3, OMe substituent at R1 (ortho substituent),
or a steric bulky t-Bu on R group. The approach may deserve further
attention as a complement to the conventional benzopyran syn-
theses because it expands the synthetic potential by wayof using the
carbonyl and ester moieties on the benzopyranones 2. Moreover, the
Scheme 6. Proposed reaction mechanism for the formation of nitro benzofuran from
1q and 1r.
rearrangement of the oxygen to give the ester group with the a-
carbanion on C-3 (intermediate VII). The strong withdrawing effect
of the para nitro substituent probably helped stabilize the given
anion through resonance effect, thus promoting the formation of
intermediate VII. The proton transfer and subsequent loss of car-
boxylate would afford the benzofuran 10. This rationale was con-
firmed by the fact that we were able to isolate the corresponding
carboxylic acid, benzoic acid 11q, and para methoxybenzoic acid 11r,
which were derived from the eliminated carboxylate anion.21 The
proposed mechanism also corresponds to the moderately electron-
withdrawing CO2Et group at R3 in which we also observed some of
benzofuran 9 (entry 12, Table 2) in 14% yield.
construction of 3-substituted
g-benzopyranone, especially those
with a substituted phenyl group, is noteworthy since the products
possess the isoflavone core, which are rich in nature and have di-
verse biological effects. Thus the present method potentially offer
practical access to both simple isoflavone natural products and ad-
vanced isoflavones, such as rotenoid natural products.22
4. Experimental section
4.1. General
The formation of benzofuran or benzopyranone products was
supported by their 1H NMR and 13C NMR spectra. The structural
difference between benzopyranones 2 and benzofurans 3 could
be deduced by the chemical shift of the carbonyl carbon and the
aromatic proton close to the carbonyl group. In benzopyranones
2, the 13C NMR of the carbonyl appeared in the range dC
176e178 ppm presumably due to the delocalization of electrons
through benzopyranone system. This chemical shift corre-
sponded to those reported carbonyl chemical shifts of 13C NMR in
benzopyranone-4-one derivatives.5 The aromatic proton on C-5
appeared far downfield in the range dH 8.1e8.4 ppm as the result
of the deshielding effect from the carbonyl group to the peri
proton. In benzofurans 3, the 13C NMR of the carbonyl located in
the range dC 190e207 ppm resembling the chemical shift of the
regular isolated ketone carbonyl. This chemical shift could be
explained by the diminishing of the delocalization through the
carbonyl group from the fully aromatized benzofuran system.
Further, the aromatic proton on C-4 was observed at 7.6e7.9 ppm
indicating the absence of a deshielding effect from the carbonyl
functionality. Additionally, all resulting structures were recon-
firmed by HMBC correlation. The benzopyranone systems showed
a strong correlation between the aromatic proton on C-5 and the
carbonyl on C-4; whereas, there was no HMBC correlation be-
tween the aromatic proton on C-4 and the carbonyl group on
benzofuran systems as shown in Fig. 1.
Commercial grade reagents and solvents were used as received from
the supplier except where indicated otherwise. 2-Iodophenol (4a),23 2-
iodo-5-methoxyphenol (4b),24 ethyl-3-hydroxy-4-iodobenzoate (4c),25
2-iodo-5-nitrophenol (4d),26 2-iodo-3,5-dimethoxyphenol (4e),27 2-
bromo-4-methoxyphenol (4f),28 4-iodobenzene-1,3-diol (4g),29 1-
ethynyl-4-methoxybenzene (7e),30 4-ethynyl-1,2-dimethoxybenzene
(7h),29 1-ethynyl-2-methoxybenzene (7i),31 and 1-ethylnyl-4-nitro-
benzene (7o), were prepared according to the literature. Tetrahydrofu-
ran (THF), dichloromethane (DCM), acetonitrile (MeCN), and toluene
were purified by pressure filtration through activated alumina. All
glassware was oven-dried at 110 ꢀC for 2 h or more. Thin layer chro-
matography was performed on Merck precoated silica gel 60F254 plates.
Silica gel 60 (Silicycle, 230e400 mesh) was used for flash column
chromatography and Silica gel 60PF254 (Merck) was used for preparative
thin layer chromatography. 1H and 13C NMR spectra were recorded in
CDCl3 or MeOD-d4 with 300 and 400 MHz NMR spectrometers. 1H NMR
and 13C NMR chemical shifts (
million(ppm), relative totetramethylsilane (TMS) as internal standard at
equal to zero ppm. Coupling constants (J) were reported in Hertz (Hz).
d) were reported in units of parts per
d
Infrared spectra measured using an FT-IR spectrometer and were re-
ported in cmꢁ1. High resolution mass spectra (HRMS) and electron-
impacted mass spectra (EI-MS) were measured on a mass spectrometer.
4.2. General procedure for preparation of ethyl-2-(2-
iodophenoxy) acetate derivatives
To a stirred solution of ortho halophenol derivative 4 (1.0 equiv)
and potassium carbonate (K2CO3) (1.0 equiv) in acetone (4 mL/
mmol of substrate) was added ethyl-2-bromoacetate (1.02 equiv) at
room temperature. The reaction mixture was stirred at reflux until
complete conversion as indicated by TLC. The resulting mixture was
allowed to cool to room temperature, filtered through Celite,
washed with excess EtOAc (three times), and concentrated under
Fig. 1. The HMBC correlation of benzopyranones 2 and benzofurans 3.

9340
S. Bensulong et al. / Tetrahedron 69 (2013) 9335e9348
reduced pressure. Unless otherwise noted, the crude residue was
purified to obtain the pure product.
158.4, 92.5, 92.1, 66.6, 61.4, 56.5, 55.5, and 14.1; HRMS calcd for
[(C12H15IO5)þNa]þ: 388.9856. Found: 388.9857.
4.2.1. Ethyl-2-(2-iodophenoxy)acetate (5a).32 2-Iodophenol (4a)
(1.3 g, 5.8 mmol), K2CO3 (0.8 g, 5.8 mmol), and ethyl-2-
bromoacetate (0.65 mL, 5.9 mmol) were used. The reaction mix-
ture was refluxed for 4 h and then worked up to obtain the title
compound 5a (1.8 g, 99% yield) as a yellow oil, which was pure to
use for the next step without further purification; IR (neat) 2981,
4.2.6. Ethyl-2-(2-bromo-4-methoxyphenoxy)acetate (5f). 2-Bromo-
4-methoxyphenol (4f) (25.0 g, 124 mmol), K2CO3 (17.0 g,
124 mmol), and ethyl-2-bromoacetate (14.0 mL, 125 mmol) were
used. The reaction mixture was refluxed for 2 h. Purification by
column chromatography (SiO2, 10% EtOAc/hexane) provided the
title compound 5f (29.1 g, 82% yield) as a yellow oil; IR (neat) 2982,
1756, 1471, and 1194 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
1.28 (t, 3H,
1755, 1733, 1490, 1192, 1083, and 1034 cmꢁ1
CDCl3)
1.28 (t, 3H, J¼7.1 Hz), 3.74 (s, 3H), 4.24 (q, 2H, J¼7.1 Hz),
4.61 (s, 2H), 6.76 (d, 1H, J¼9.0 Hz), 6.84 (d, 1H, J¼9.0 Hz), and 7.10 (s,
1H); 13C NMR (75 MHz, CDCl3)
168.5, 154.9, 148.7, 118.8, 115.7,
;
1H NMR (300 MHz,
J¼7.1 Hz), 4.25 (q, 2H, J¼7.1 Hz), 4.68 (s, 2H), 6.72 (d, 1H, J¼7.8 Hz),
d
6.73 (t, 1H, J¼7.6 Hz), 7.26 (td, 1H, J¼7.8 and 1.5 Hz), and 7.77 (d, 1H,
J¼7.6 Hz); 13C NMR (75 MHz, CDCl3)
d
167.9, 156.2, 139.3, 129.0,
d
123.1, 112.0, 86.0, 65.9, 61.0, and 13.8; HRMS calcd for [(C10H11IO3)þ
113.5, 113.1, 67.3, 61.2, 55.6, and 14.0; HRMS calcd for
H]þ: 306.9826. Found: 306.9822.
[(C11H13BrO4)þNa]þ: 310.9889. Found: 310.9879.
4.2.2. Ethyl-2-(2-iodo-5-methoxyphenoxy)acetate (5b). 2-Iodo-5-
methoxyphenol (4b) (3.9 g, 15.6 mmol), K2CO3 (2.2 g, 15.6 mmol),
and ethyl-2-bromoacetate (1.8 mL, 16.0 mmol) were used. The re-
action mixture was refluxed for 6 h. Purification by column chro-
matography (SiO2, 10% EtOAc/hexane) provided the title compound
5b (4.5 g, 86% yield) as a yellow oil; IR (neat) 2980, 1755, 1578, 1304,
4.3. Ethyl-2-(2-iodo-5-(tosyloxy)phenoxy)acetate (5g)
To a stirred solution of 4-iodobenzene-1,3-diol (4g) (1.2 g,
5.0 mmol) and potassium carbonate (K2CO3) (2.1 g, 14.9 mmol) in
20 mL of acetone was added p-toluene sulfonylchloride (TsCl)
(0.9 g, 5.0 mmol) at room temperature. The reaction mixture was
and 1164 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
1.28 (t, 3H, J¼7.1 Hz),
stirred at reflux for 20 h, and then 577 mL (5.21 mmol) of ethyl-2-
3.74 (s, 3H), 4.24 (q, 2H, J¼7.1 Hz), 4.64 (s, 2H), 6.32 (s, 1H), 6.34 (d,
bromoacetate was added. The resulting mixture was stirred for an
additional 3 h, then allowed to cool to room temperature, filtered
through Celite, washed with excess EtOAc (three times), and con-
centrated under reduced pressure. Purification by column chro-
matography (SiO2, 5% EtOAc/hexane) provided the title compound
5g (1.2 g, 49% yield) as a pale yellow oil; IR (neat) 2982, 1756, 1590,
1H, J¼8.5 Hz), and 7.61 (d, 1H, J¼8.5 Hz); 13C NMR (75 MHz, CDCl3)
d
167.9, 160.9, 157.1, 139.2, 108.0, 100.3, 74.9, 66.1, 61.2, 55.2, and
13.9; HRMS calcd for [(C11H13IO4)þH]þ: 336.9931. Found:
336.9943.
4.2.3. Ethyl-3-(2-ethoxy-2-oxoethoxy)-4-iodobenzoate (5c). Ethyl-
3-hydroxy-4-iodobenzoate (4c) (220 mg, 0.75 mmol), K2CO3
1471, 1373, 1192, 1178, 1091, and 950 cmꢁ1
CDCl3)
;
1H NMR (300 MHz,
1.32 (t, 3H, J¼7.1 Hz), 2.47 (s, 3H), 4.37 (q, 2H, J¼7.1 Hz),
d
(104 mg, 0.75 mmol), and ethyl-2-bromoacetate (54
m
L,
4.59 (s, 2H), 6.33 (dd, 1H, J¼8.5 and 1.7 Hz), 6.46 (s, 1H), 7.32 (d, 2H,
0.77 mmol) were used. The reaction mixture was refluxed for 6 h.
Purification by column chromatography (SiO2, 10% EtOAc/hexane)
provided the title compound 5c (281 mg, 99% yield) as a yellow
J¼8.1 Hz), 7.66 (d, 1H, J¼8.5 Hz), and 7.70 (d, 2H, J¼8.1 Hz); 13C NMR
(75 MHz, CDCl3) d 167.5,157.3, 150.5,145.7, 139.7, 129.9, 128.6, 128.5,
117.0, 107.3, 84.1, 66.3, 61.7, 21.7, and 14.1; HRMS calcd for
oil; IR (neat) 2988, 2924, 1756, 1714, and 1239 cmꢁ1
;
1H NMR
[(C17H17IO6S)þNa]þ: 498.9683. Found: 498.9665.
(300 MHz, CDCl3)
d
1.31 (t, 3H, J¼7.1 Hz), 1.38 (t, 3H, J¼7.1 Hz), 4.28
(q, 2H, J¼7.1 Hz), 4.36 (q, 2H, J¼7.1 Hz), 4.75 (s, 2H), 7.35 (s, 1H),
4.4. General procedure for Sonogashira coupling
7.41 (d, 1H, J¼8.0 Hz), and 7.87 (d, 1H, J¼8.0 Hz); 13C NMR
(75 MHz, CDCl3)
d
167.8, 165.7, 156.8, 139.8, 132.0, 124.2, 112.5,
To a solution of the aryl halide substrate (1.0 equiv) in a dry
solution of Et3N (2 mL/mmol of substrate) and MeCN (2 mL/mmol
of substrate) was added the terminal alkyne substrate (1.1 equiv),
copper iodide (CuI) (0.1 equiv), and tetrakis (triphenylphosphine)
palladium [Pd(PPh3)4] (0.05 equiv). The reaction mixture was stir-
red at reflux under argon atmosphere overnight. The resulting
mixture was filtered through Celite and washed with excess EtOAc.
The combined organic solvent was removed under reduced pres-
sure and the crude product was purified to provide the desire
product.
93.0, 66.3, 61.5, 61.3, 14.3 and 14.1; HRMS calcd for [(C13H15IO5)þ
Na]þ: 400.9856. Found: 400.9856.
4.2.4. Ethyl-2-(2-iodo-5-nitrophenoxy)acetate
(5d). 2-Iodo-5-
nitrophenol (4d) (1.6 g, 6.1 mmol), K2CO3 (0.8 g, 6.1 mmol), and
ethyl-2-bromoacetate (0.7 mL, 6.2 mmol) were used. The reaction
mixture was refluxed for 6 h. Purification by column chromatog-
raphy (SiO2, 10% EtOAc/hexane) provided the title compound 5d
(2.0 g, 92% yield) as a yellow solid; mp 84e86 ꢀC; IR (neat) 2922,
1753, 1524, 1467, and 1204 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 1.42
(t, 3H, J¼7.0 Hz), 4.39 (q, 2H, J¼7.0 Hz), 4.81 (s, 2H), 7.52 (s, 1H),
4.4.1. Ethyl-2-(2-(phenylethynyl)phenoxy)acetate (6a).8 Compound
5a (2.00 g, 6.53 mmol), phenylacetylene (730 mg, 7.19 mmol), CuI
(124 mg, 0.65 mmol), and Pd(PPh3)4 (376 mg, 0.33 mmol) were
used. Purification by column chromatography (SiO2, 10% EtOAc/
hexane) provided the title compound 6a (1.80 g, 100% yield) as
7.64 (d, 1H, J¼8.3 Hz), and 8.01 (d, 1H, J¼8.3 Hz); 13C NMR
(75 MHz, CDCl3)
d 168.4, 157.6, 149.0, 140.6, 117.9, 107.1, 97.0, 66.4,
61.4, and 14.5; HRMS calcd for [(C10H10INO5)]: 350.9598. Found:
350.9598.
a yellow oil; IR (neat) 2982, 1757, 1497, and 1193 cmꢁ1
(300 MHz, CDCl3)
;
1H NMR
4.2.5. Ethyl-2-(2-iodo-3,5-dimethoxyphenoxy)acetate (5e). 2-Iodo-
3,5-dimethoxyphenol (4e) (60 mg, 0.21 mmol), K2CO3 (29 mg,
0.21 mmol), and ethyl 2-bromoacetate (38 mg, 0.22 mmol) were
used. The reaction mixture was refluxed for 3 h. Purification by
preparative thin layer chromatography (SiO2, 20% EtOAc/hexane)
provided the title compound 5e (69 mg, 90% yield) as a yellow
solid; mp 74e75 ꢀC; IR (neat) 2793, 1755, 1582, 1199, 1162, 1127, and
d
1.26 (t, 3H, J¼7.1 Hz), 4.25 (q, 2H, J¼7.1 Hz), 4.72
(s, 2H), 6.81 (d, 1H, J¼8.3 Hz), 6.97 (t, 1H, J¼7.5 Hz), 7.22e7.35 (m,
4H), 7.50 (dd,1H, J¼7.5 and 1.7 Hz), and 7.54e7.58 (m, 2H); 13C NMR
(75 MHz, CDCl3) d 168.5,158.5,135.2,133.5,131.6,129.4,128.2,128.1,
123.6, 121.8, 113.4, 93.9, 85.4, 66.6, 61.1, and 14.0; HRMS calcd for
[(C18H16O3)þH]þ: 281.1172. Found: 281.1170.
1017 cmꢁ1; 1H NMR (300 MHz, CDCl3)
(s, 3H), 3.86 (s, 3H), 4.26 (q, 2H, J¼7.1 Hz), 4.66 (s, 2H), 6.04 (s, 1H),
and 6.16 (s, 1H); 13C NMR (75 MHz, CDCl3)
168.3, 161.9, 160.0,
d
1.30 (t, 3H, J¼7.1 Hz), 3.79
4.4.2. Ethyl-2-(2-(hex-1-ynyl)phenoxy)acetate (6b). Compound 5a
(1.25 g, 4.08 mmol), hex-1-yne (369 mg, 4.49 mmol), CuI (78 mg,
0.41 mmol), and Pd(PPh3)4 (228 mg, 0.20 mmol) were used.
d

S. Bensulong et al. / Tetrahedron 69 (2013) 9335e9348
9341
Purification by column chromatography (SiO2, 10% EtOAc/hexane)
provided the title compound 6b (1.07 g, 100% yield) as a yellow oil;
149.8, 145.6, 133.8, 131.6, 129.8, 128.5, 128.4, 128.2, 123.0, 121.1,
115.3, 112.4, 107.6, 94.8, 84.1, 66.1, 61.5, 21.6, and 14.1; HRMS calcd
for [(C25H22O6S)þH]þ: 451.1210. Found: 451.1195.
IR (neat) 2932, 1759, 1736, 1491, 1189, and 749 cmꢁ1 1H NMR
;
(300 MHz, CDCl3)
d
0.75 (t, 3H, J¼7.0 Hz), 1.28 (t, 3H, J¼7.1 Hz), 1.50
(sext, 2H, J¼7.0 Hz), 1.62 (pent, 2H, J¼7.0 Hz), 2.46 (t, 2H, J¼7.0 Hz),
4.26 (q, 2H, J¼7.1 Hz), 4.69 (s, 2H), 6.77 (d, 1H, J¼8.0 Hz), 6.93 (t, 1H,
J¼7.5 Hz), 7.19 (t, 1H, J¼8.0 Hz), and 7.39 (d, 1H, J¼7.5 Hz); 13C NMR
4.4.7. Ethyl-2-(2-((3,4-dimethoxyphenyl)ethynyl)-5-(tosyloxy) phe-
noxy)acetate (6h). Compound 5g (1.00 g, 2.10 mmol), 4-ethynyl-1,2-
dimethoxybenzene (386 mg, 2.31 mmol), CuI (41 mg, 0.21 mmol),
and Pd(PPh3)4 (121 mg, 0.11 mmol) were used. Purification by col-
umn chromatography (SiO2, 10% EtOAc/hexane) provided the title
compound 6h (890 mg, 81% yield) as a light brown oil; IR (neat)
(75 MHz, CDCl3)
d 168.7, 158.2, 133.7, 128.5, 121.6, 114.2, 113.0, 95.1,
76.2, 66.3, 61.2, 30.8, 21.9, 19.4, 14.1, and 13.6; HRMS calcd for
[(C16H20O3)þH]þ: 261.1485. Found: 261.1474.
2967, 2214, 1756, 1514, 1191, 1178, 1133, and 1023 cmꢁ1
(300 MHz, CDCl3)
;
1H NMR
4.4.3. Ethyl-2-(2-(3-(tetrahydro-2H-pyran-2-yloxy)prop-1-ynyl)
phenoxy)acetate (6c). Compound 5a (125 mg, 0.41 mmol), 2-(prop-
2-ynyloxy)tetrahydro-2H-pyran (63 mg, 0.45 mmol), CuI (8 mg,
40 mmol), and Pd(PPh3)4 (24 mg, 20 mmol) were used. Purification
by column chromatography (SiO2, 10% EtOAc/hexane) provided the
d
1.29 (t, 3H, J¼7.1 Hz), 2.43 (s, 3H), 3.88 (s, 3H),
3.89 (s, 3H), 4.25 (q, 2H, J¼7.1 Hz), 4.60 (s, 2H), 6.51 (s, 1H), 6.55 (d,
1H, J¼8.4 Hz), 6.82 (d, 1H, J¼8.4 Hz), 7.07 (s, 1H), 7.13 (d, 1H,
J¼8.4 Hz), 7.30 (d, 2H, J¼8.1 Hz), 7.36 (d, 1H, J¼8.4 Hz), and 7.68 (d,
2H, J¼8.1 Hz); 13C NMR (75 MHz, CDCl3)
d 167.7, 158.5, 149.4, 148.4,
title compound 6c (93 mg, 71% yield)/as a yellow oil; IR (neat) 2939,
145.5, 133.4, 131.7, 129.6, 128.3, 128.2, 124.8, 115.1, 115.0, 114.1, 112.5,
110.8, 107.3, 94.9, 82.5, 65.9, 61.3, 55.7, 55.6, 21.5, and 13.9; HRMS
calcd for [(C27H26O8S)þH]þ: 511.1421. Found: 511.1432.
1757, 1491, and 1195 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 1.29 (t, 3H,
J¼7.1 Hz), 1.53e1.81 (m, 6H), 3.53e3.60 (m, 1H), 3.86e3.94 (m, 1H),
4.26 (q, 2H, J¼7.1 Hz), 4.54 (d, 2H, J¼3.2 Hz), 4.70 (s, 2H), 4.95 (t, 1H,
J¼3.2 Hz), 6.78 (d, 1H, J¼7.5 Hz), 6.94 (td, 1H, J¼7.5 and 0.85 Hz),
7.22e7.28 (m, 1H), and 7.44 (dd, 1H, J¼7.5 and 1.6 Hz); 13C NMR
4.4.8. Ethyl-2-(2-((4-methoxyphenyl)ethynyl)phenoxy)acetate
(6j).8 Compound 5a (500 mg, 1.63 mmol), 1-ethynyl-4-methoxy
benzene (240 mg, 1.80 mmol), CuI (31 mg, 0.16 mmol), and
(75 MHz, CDCl3)
d 168.6, 158.6, 134.0, 129.6, 121.6, 112.7, 96.7, 89.7,
81.7, 66.2, 62.0, 61.3, 54.9, 30.3, 29.6, 25.4, 19.1, and 14.1; HRMS
Pd(PPh3)4 (95 mg, 89 mmol) were used. Purification by column chro-
matography (SiO2,15% EtOAc/hexane) provided the title compound 6j
(433 mg, 85% yield) as a yellow oil; IR (neat) 2924, 1758, 1510, and
calcd for [(C18H22O5)þNa]þ: 341.1359. Found: 341.1363.
4.4.4. Ethyl-2-(5-methoxy-2-(phenylethynyl)phenoxy)acetate
(6d). Compound 5b (500 mg, 1.49 mmol), phenylacetylene
(168 mg, 1.64 mmol), CuI (29 mg, 0.15 mmol), and Pd(PPh3)4
1194 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
1.29 (t, 3H, J¼7.1 Hz), 3.82 (s,
3H), 4.27 (q, 2H, J¼7.1 Hz), 4.74 (s, 2H), 6.85 (t, 1H, J¼8.3 Hz), 6.87 (d,
2H, J¼8.3 Hz), 6.98 (t,1H, J¼7.5 Hz), 7.23 (d,1H, J¼8.8 Hz), and 7.50 (d,
(87 mg, 74
mmol) were used. Purification by column chromatog-
3H, J¼7.5 Hz); 13C NMR (75 MHz, CDCl3)
d 168.8, 159.6, 158.3, 133.4,
raphy (SiO2, 10% EtOAc/hexane) provided the title compound 6d
133.1, 129.2, 121.8, 115.6, 113.9, 113.2, 112.6, 94.0, 84.0, 66.5, 61.3, 55.3,
(465 mg,100% yield) as a yellow oil; IR (neat) 2981,1759,1610,1508,
and14.2; HRMS calcd for [(C19H18O4)þH]þ: 311.1278. Found:311.1283.
1301, 1195, and 1167 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 1.17 (t, 3H,
J¼7.1 Hz), 3.67 (s, 3H), 4.15 (q, 2H, J¼7.1 Hz), 4.61 (s, 2H), 6.28 (s,1H),
4.4.9. Ethyl-2-(2-((3,4-dimethoxyphenyl)ethynyl)phenoxy)acetate
(6k). Compound 5a (1.00 g, 3.27 mmol), 4-ethynyl-1,2-dimethoxy
benzene (583 mg, 3.59 mmol), CuI (62 mg, 0.33 mmol), and
Pd(PPh3)4 (182 mg, 0.16 mmol) were used. Purification by column
chromatography (SiO2, 15% EtOAc/hexane) provided the title com-
pound 6k (1.03 g, 93% yield) as a pale yellow solid; mp 67e68 ꢀC; IR
(neat) 2972, 2837, 2208,1755,1514,1218,1195,1109, and 1019 cmꢁ1;1H
6.42 (d, 1H, J¼8.5 Hz), 7.19 (t, 3H, J¼6.8 Hz), 7.32 (d, 1H, J¼8.5 Hz),
and 7.44 (d, 2H, J¼6.8 Hz); 13C NMR (75 MHz, CDCl3)
d 168.4, 160.7,
159.4, 134.2, 131.3, 128.1, 127.7, 123.7, 106.3, 105.7, 100.5, 92.4, 85.3,
66.2, 61.2, 55.3, and 14.0; HRMS calcd for [(C19H18O4)þNa]þ:
333.1097. Found: 333.1094.
4.4.5. Ethyl-2-(5-methoxy-2-((4-methoxyphenyl)ethynyl)phenoxy)
acetate (6e). Compound 5b (500 mg, 1.49 mmol), 1-ethynyl-4-
methoxybenzene (220 mg, 1.64 mmol), CuI (29 mg, 0.15 mmol),
NMR (300 MHz, CDCl3)
d
1.27 (t, 3H, J¼7.1 Hz), 3.87 (s, 3H), 3.89 (s, 3H),
4.25 (q, 2H, J¼7.1 Hz), 7.73 (s, 2H), 6.81 (d, 2H, J¼8.3 Hz), 6.95 (t, 1H,
J¼7.5 Hz), 7.11 (s, 1H), 7.15 (d, 1H, J¼8.3 Hz), 7.25 (t, 1H, J¼7.5 Hz), and
and Pd(PPh3)4 (87 mg, 74
mmol) were used. Purification by column
7.50 (d, 1H, J¼7.5 Hz); 13C NMR (75 MHz, CDCl3)
d 168.3, 158.0, 149.2,
chromatography (SiO2, 10% EtOAc/hexane) provided the title com-
148.3,133.1,129.0,124.6,121.5,115.4,114.2,113.4,112.6,110.7, 93.9, 83.6,
66.0, 60.9, 55.6, 55.5, and 13.8; HRMS calcd for [(C20H20O5)þNa]þ:
363.1203. Found: 363.1200.
pound 6e (436 mg, 85% yield) as a colorless oil; IR (neat) 2937, 1757,
1610, 1515, 1246, and 1194 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 1.30
(t, 3H, J¼7.1 Hz), 3.80 (s, 3H), 3.82 (s, 3H), 4.27 (q, 2H, J¼7.1 Hz), 4.72
(s, 2H), 6.39 (s, 1H), 6.53 (d, 1H, J¼8.5 Hz), 6.86 (d, 2H, J¼8.5 Hz),
7.41 (d, 1H, J¼8.5 Hz), and 7.41 (d, 2H, J¼8.5 Hz); 13C NMR (75 MHz,
4.4.10. Ethyl-3-(2-ethoxy-2-oxoethoxy)-4-(phenylethynyl)benzoate
(6l). Compound 5c (936 mg, 2.48 mmol), phenylacetylene (280 mg,
2.79 mmol), CuI (48 mg, 0.25 mmol), and Pd(PPh3)4 (144 mg,
0.12 mmol) were used. Purification by column chromatography
(SiO2, 7% EtOAc/hexane) provided the title compound 6l (877 mg,
100% yield) as a red oil; IR (neat) 2982, 1760, 1717, 1417, 1291, and
CDCl3)
d 168.6, 160.5, 159.3, 159.2, 134.1, 132.8, 115.9, 113.8, 106.5,
106.2, 100.7, 92.4, 83.9, 66.4, 61.3, 55.4, 55.2, and 14.1; HRMS calcd
for [(C20H20O5)þH]þ: 341.1384. Found: 341.1374.
4.4.6. Ethyl-2-(2-(phenylethynyl)-5-(tosyloxy)phenoxy)acetate
(6g). Compound 5g (1.10 g, 2.30 mmol), phenylacetylene (252 mg,
2.54 mmol), CuI (42 mg, 0.23 mmol), and Pd(PPh3)4 (125 mg,
0.12 mmol) were used. The reaction mixture was refluxed over-
night under argon atmosphere and then worked up to give the
crude compound. Purification by column chromatography (SiO2,
10% EtOAc/hexane) provided the title compound 6g (1.00 g, 100%
yield) as a yellow oil; IR (neat) 2983, 1757, 1594, 1501, 1374, 1179,
1199 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
1.30 (t, 3H, J¼7.0 Hz), 1.39
(t, 3H, J¼7.0 Hz), 4.29 (q, 2H, J¼7.0 Hz), 4.37 (q, 2H, J¼7.0 Hz), 4.79 (s,
2H), 7.35 (br s, 3H), 7.48 (br s, 1H), 7.57 (br t, 3H, J¼7.9 Hz), and 7.68
(d, 1H, J¼7.9 Hz); 13C NMR (75 MHz, CDCl3)
d 168.2, 165.8, 158.1,
133.3, 131.8, 131.1, 128.7, 128.3, 123.0, 122.8, 118.1, 113.1, 96.7, 84.8,
66.1, 61.5, 61.3, 14.3, and 14.2; HRMS alcd for [(C21H20O5)þNa]þ:
375.1203. Found: 375.1208.
1192, 1091, and 953 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
1.29 (t, 3H,
4.4.11. Ethyl-2-(2-(3,3-dimethylbut-1-ynyl)phenoxy)acetate
J¼7.1 Hz), 2.43 (s, 3H), 4.26 (q, 2H, J¼7.1 Hz), 4.61 (s, 2H), 6.54 (s,
(6m). Compound 5a (480 mg, 1.57 mmol), 3,3-dimethylbut-1-yne
1H), 6.55 (d, 1H, J¼8.6 Hz), 7.20e7.45 (m, 6H), 7.50 (br s, 2H), and
(200
mL, 1.72 mmol), CuI (30 mg, 0.16 mmol), and Pd(PPh3)4
7.69 (d, 2H, J¼7.9 Hz); 13C NMR (75 MHz, CDCl3)
d
167.8, 158.9,
(87 mg, 78
mmol) were used. Purification by column

9342
S. Bensulong et al. / Tetrahedron 69 (2013) 9335e9348
chromatography (SiO2, 10% EtOAc/hexane) provided the title com-
methoxybenzene (63 mg, 0.31 mmol), CuI (7 mg, 28
mmol), and
pound 6m (371 mg, 90% yield) as a pale yellow oil; IR (neat) 2969,
Pd(PPh3)4 (22 mg, 14 mol) were used. Purification by column
chromatography (SiO2, 10% EtOAc/hexane) provided the title com-
m
1760, 1492, and 1188 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
1.30 (t, 3H,
J¼7.1 Hz), 1.34 (s, 9H), 4.27 (q, 2H, J¼7.1 Hz), 4.67 (s, 2H), 6.81 (d, 1H,
pound 6r (131 mg, 96% yield) as a yellow oil; IR (neat) 2927, 2212,
J¼8.0 Hz), 6.93 (t, 1H, J¼7.5 Hz), 7.19 (t, 1H, J¼8.0 Hz), and 7.36 (d,
1755, 1513, 1343, and 1200 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 1.33
1H, J¼7.5 Hz); 13C NMR (75 MHz, CDCl3)
d
168.8, 158.3, 133.7, 128.6,
(t, 3H, J¼7.1 Hz), 3.85 (s, 3H), 4.31 (q, 2H, J¼7.1 Hz), 4.82 (s, 2H), 6.90
121.9, 114.0, 112.4, 103.4, 74.7, 66.7, 61.2, 31.0, 28.2, and 14.2; HRMS
(d, 2H, J¼8.4 Hz), 7.54 (d, 2H, J¼8.4 Hz), 7.61 (d, 1H, J¼8.4 Hz), 7.66
calcd for [(C16H20O3)þH]þ: 261.1485. Found: 261.1484.
(s, 1H), and 7.88 (d, 1H, J¼8.4 Hz); 13C NMR (75 MHz, CDCl3)
d 167.6,
160.4, 158.2, 147.4, 133.5, 133.3, 121.0, 116.8, 114.5, 114.1, 107.4, 99.6,
82.9, 66.2, 61.7, 55.3, and 14.1; HRMS calcd for [(C19H17NO6)þH]þ:
356.1129 Found: 356.1126.
4.4.12. Ethyl-2-(2-((3,4-dimethoxyphenyl)ethynyl)-3,5-dimethoxy
phenoxy)acetate (6n). Compound 5e (57 mg, 0.16 mmol), 4-
ethynyl-1,2-dimethoxybenzene (28 mg, 0.17 mmol), CuI (3 mg,
15
mmol), and Pd(PPh3)4 (9 mg, 8
mmol) were used. Purification by
4.4.17. Ethyl-2-(5-nitro-2-((4-nitrophenyl)ethynyl)phenoxy) acetate
preparative thin layer chromatography (SiO2, 10% EtOAc/hexane)
provided the title compound 6n (39 mg, 61% yield) as a yellow
solid; mp 131e132 ꢀC; IR (neat) 2915, 2836, 1761, 1517, 1202, 1145,
(6s). Compound5d (100 mg, 0.28 mmol),1-ethynyl-4-nitrobenzene
(62 mg, 0.31 mmol), CuI (7 mg, 28
mmol), and Pd(PPh3)4 (22 mg,
14 mol) were used. Purification by column chromatography (SiO2,
m
and 1020 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
1.37 (t, 3H, J¼7.1 Hz),
10% EtOAc/hexane) provided the title compound 6s (62 mg, 44%
3.80 (s, 3H), 3.88 (s, 6H), 3.90 (s, 3H), 4.25 (q, 2H, J¼7.1 Hz), 4.71 (s,
yield) as a yellow oil; IR (neat) 3112, 2925, 1739, 1595, 1516, and
2H), 6.05 (s, 1H), 6.16 (s, 1H), 7.82 (d, 1H, J¼8.3 Hz), 7.12 (s, 1H), and
1343 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
1.34 (t, 3H, J¼7.2 Hz), 4.33 (q,
7.17 (d, 1H, J¼8.3 Hz); 13C NMR (75 MHz, CDCl3)
d
168.4, 161.8, 161.0,
2H, J¼7.2 Hz), 4.84 (s, 2H), 7.68 (d, 2H, J¼7.1 Hz), 7.75 (d, 2H,
160.4, 148.9, 148.3, 124.6, 116.3, 114.2, 110.7, 96.7, 95.6, 92.5, 91.6,
79.9, 66.4, 61.1, 56.0, 55.8, 55.7, 55.3, and 14.0; HRMS calcd for
[(C22H24O7)þNa]þ: 423.1412. Found: 423.1418.
J¼8.3 Hz), 7.92 (d,1H, J¼8.5 Hz), and 8.26 (d, 2H, J¼8.3 Hz); 13C NMR
(75 MHz, CDCl3) d 167.3,158.8, 148.5,147.5,133.9,132.6,129.3,123.7,
119.1, 116.7, 107.0, 96.3, 88.5, 65.9, 61.9 and 14.1; HRMS calcd for
[(C18H14N2O7)þH]þ: 370.0796. Found: 370.0795.
4.4.13. Ethyl-2-(2-((4-nitrophenyl)ethynyl)phenoxy)acetate
(6o). Compound 5a (100 mg, 0.33 mmol), 1-ethynyl-4-nitrobenzene
4.4.18. (2-((Trimethylsilyl)ethynyl)phenoxy)methyl propionate (6t).32b
(50 mg, 0.36 mmol), CuI (6 mg, 32
mmol), and Pd(PPh3)4 (19 mg,
Compound 5a (71 mg, 0.23 mmol), ethynyltrimethylsilane (36
mL,
16 mol) were used. Purification by column chromatography (SiO2
m
0.26 mmol), CuI (4 mg, 23 mol), and Pd(PPh3)4 (13 mg, 11 mol)
m
m
10%EtOAc/hexane)providedthetitlecompound6o(85 mg, 79% yield)
were used. Purification by column chromatography (SiO2, 10% EtOAc/
hexane) provided the title compound 6t (53 mg, 83% yield) as a yel-
as a yellow oil; IR (neat) 2924, 1756, 1592, 1342, and 1193 cmꢁ1; 1H
NMR (300 MHz, CDCl3)
d
1.31 (t, 3H, J¼7.0 Hz), 4.30 (q, 2H, J¼7.0 Hz),
low oil; IR (neat) 2961, 2158, 1760, 1489, and 1189 cmꢁ1 1H NMR
;
4.74 (s, 2H), 6.83 (d, 1H, J¼8.3 Hz), 7.02 (t, 1H, J¼7.5 Hz), 7.34 (t, 1H,
J¼8.0 Hz), 7.53 (d,1H, J¼8.0 Hz), 7.71 (d, 2H, J¼8.0 Hz), and 8.21 (d, 2H,
(300 MHz, CDCl3)
d
0.27 (s, 9H), 1.30 (t, 3H, J¼7.1 Hz), 4.27 (q, 2H,
J¼7.1 Hz), 4.70 (s, 2H), 6.79 (d, 1H, J¼8.2 Hz), 6.94 (td, 1H, J¼7.6 and
J¼8.0 Hz); 13C NMR (75 MHz, CDCl3)
d 168.4,158.7,146.9,139.8,135.2,
0.9 Hz), 7.24 (td, 1H, J¼8.2 and 1.7 Hz), and 7.45 (dd, 1H, J¼7.6 and
133.8, 132.3, 130.7, 123.6, 121.8, 112.4, 92.1, 91.0, 66.0, 61.5, and 14.1;
1.7 Hz); 13C NMR (75 MHz, CDCl3)
d 168.5, 158.8, 134.1, 129.7, 121.7,
HRMS calcd for [(C18H15NO5)þNa]þ: 348.0842. Found: 348.0838.
113.3, 100.7, 99.0, 66.4, 61.2, 29.6, 14.1, and ꢁ0.1; HRMS calcd for
[(C15H20O3Si)þH]þ: 277.1255 Found: 277.1247.
4.4.14. Ethyl-2-(5-methoxy-2-((4-nitrophenyl)ethynyl)phenoxy) ac-
etate (6p). Compound 5b (500 mg, 1.49 mmol), 1-ethynyl-4-
nitrobenzene (243 mg, 1.64 mmol), CuI (29 mg, 0.15 mmol), and
4.5. Ethyl-2-(2-(hex-1-ynyl)-4-methoxyphenoxy)acetate (6f)
Pd(PPh3)4 (87 mg, 74
chromatography (SiO2, 10% EtOAc/hexane) provided the title com-
m
mol) were used. Purification by column
To a solution of compound 5f (2.00 g, 6.92 mmol) in a dry so-
lution of Et3N (14 mL) and MeCN (14 mL) were added hex-1-yne
(1.6 mL, 13.8 mmol), CuI (66 mg, 0.35 mmol), and Pd(PPh3)4
(192 mg, 0.17 mmol). The reaction mixture was stirred at reflux
under argon atmosphere overnight. The resulting mixture was then
filtered through Celite and washed with excess EtOAc. All volatile
organic solvent was removed under reduced pressure and the
crude product was purified by column chromatography (SiO2, 15%
EtOAc/hexane) to provide the title compound 6f (1.0 g, 51% yield) as
a yellow oil; IR (neat) 2933, 1758, 1735, 1496, 1187, 1073, 1035 and
pound 6p (404 mg, 76% yield) as an orange oil; IR (neat) 2980, 2937,
2212, 1758, 1591, 1514, and 1341 cmꢁ1 1H NMR (300 MHz, CDCl3)
;
d
1.32 (t, 3H, J¼7.1 Hz), 3.83 (s, 3H), 4.30 (q, 2H, J¼7.1 Hz), 4.72 (s,
2H), 6.38 (s, 1H), 6.56 (d, 1H, J¼8.5 Hz), 7.45 (d, 1H, J¼8.5 Hz), 7.67
(d, 2H, J¼8.4 Hz), and 8.20 (d, 2H, J¼8.4 Hz); 13C NMR (75 MHz,
CDCl3)
d 168.2, 161.8, 159.9, 146.6, 134.7, 132.0, 131.0, 123.6, 106.4,
104.7, 100.1, 91.5, 91.1, 66.0, 61.5, 55.6, and 14.2; HRMS calcd for
[(C19H17NO6)þH]þ: 356.1129. Found: 356.1127.
801 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
0.95 (t, 3H, J¼7.0 Hz), 1.29 (t,
4.4.15. Ethyl-2-(5-nitro-2-(phenylethynyl)phenoxy)acetate
(6q). Compound 5d (220 mg, 0.63 mmol), phenylacetylene (70 mg,
0.69 mmol), CuI (12 mg, 63
3H, J¼7.1 Hz), 1.40e1.70 (m, 4H), 2.46 (t, 2H, J¼7.0 Hz), 3.75 (s, 3H),
4.25 (q, 2H, J¼7.1 Hz), 4.65 (s, 2H), 6.74 (d, 1H, J¼9.1 Hz), 6.80 (d, 1H,
mmol), and Pd(PPh3)4 (36 mg, 31
mmol)
J¼9.1 Hz), and 6.91 (s, 1H); 13C NMR (75 MHz, CDCl3)
d 169.1, 154.4,
were used. Purification by column chromatography (SiO2, 10%
EtOAc/hexane) provided the title compound 6q (171 mg, 84% yield)
as a yellow oil; IR (neat) 2984, 2216, 1756, 1519, 1339, and
152.9, 118.2, 116.1, 115.5, 114.6, 95.3, 76.2, 67.7, 61.1, 55.7, 30.8, 22.0,
19.4, 14.1, and 13.6; HRMS calcd for [(C17H22O4)þNa]þ: 313.1410.
Found: 313.1411.
1202 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
1.33 (t, 3H, J¼7.1 Hz), 4.32
(q, 2H, J¼7.1 Hz), 4.83 (s, 2H), 7.39 (br s, 3H), 7.57e7.64 (m, 3H), 7.66
4.6. Ethyl-2-(2-((2-methoxyphenyl)ethynyl)phenoxy)acetate
(6i)
(s, 1H), and 7.89 (d, 1H, J¼8.5 Hz); 13C NMR (75 MHz, CDCl3)
d 167.5,
158.3, 147.6, 133.5, 131.8, 129.0, 128.3, 122.3, 120.3, 116.6, 107.2, 98.9,
83.8, 66.0, 61.6, and 14.0; HRMS calcd for [(C18H15NO5)þH]þ:
326.1023. Found: 326.1023.
To a solution of compound 5a (100 mg, 0.33 mmol) in a dry
solution of Et3N (0.7 mL) and MeCN (0.7 mL) were added 1-ethynyl-
2-methoxybenzene (48 mg, 0.36 mmol), CuI (13 mg, 65
Pd(PPh3)4 (38 mg, 33 mol). The reaction mixture was stirred at
reflux under argon atmosphere for 2 days. The resulting mixture
mmol), and
4.4.16. Ethyl-2-(2-((4-methoxyphenyl)ethynyl)-5-nitrophenoxy) ac-
etate (6r). Compound 5d (100 mg, 0.28 mmol), 1-ethynyl-4-
m

S. Bensulong et al. / Tetrahedron 69 (2013) 9335e9348
9343
was filtered through Celite and washed with excess EtOAc. The
combined organic phase was concentrated under reduced pressure.
Purification by flash silica gel column chromatography using 10%
EtOAc/hexane mixture as an eluent provided the title compound 6i
(66 mg, 65% yield) as a yellow oil; IR (neat) 2928, 1756, 1498, and
755 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
0.95 (t, 3H, J¼7.5 Hz), 1.28 (t,
3H, J¼7.1 Hz),1.41 (sext, 2H, J¼7.5 Hz),1.69 (pent, 2H, J¼7.5 Hz), 2.90
(t, 2H, J¼7.5 Hz), 4.25 (q, 2H, J¼7.1 Hz), 4.59 (s, 2H), 6.87 (d, 1H,
J¼7.6 Hz), 7.13 (t,1H, J¼7.6 Hz), 7.54 (t,1H, J¼7.6 Hz), and 7.82 (d,1H,
J¼7.6 Hz); 13C NMR (75 MHz, CDCl3)
d 203.0, 194.8, 167.5, 158.0,
1197 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
1.29 (t, 3H, J¼7.1 Hz), 3.93
135.5, 130.8, 124.0, 122.5, 112.8, 65.9, 61.5, 37.0, 24.6, 22.2, 14.0, and
(s, 3H), 4.27 (q, 2H, J¼7.1 Hz), 4.79 (s, 2H), 6.88 (t,1H, J¼8.2 Hz), 6.95
(d,1H, J¼7.2 Hz), 7.00 (t, 2H, J¼7.5 Hz), 7.26 (t,1H, J¼10.2 Hz), 7.29 (t,
1H, J¼8.2 Hz), and 7.54 (d, 2H, J¼7.5 Hz); 13C NMR (75 MHz, CDCl3)
13.8; HRMS calcd for [(C16H20O5)þNa]þ: 315.1203. Found: 315.1199.
4.8.3. Ethyl-2-(2-(2-oxo-3-(tetrahydro-2H-pyran-2yloxy) propanoyl)
phenoxy)acetate (1c). Alkyne 6c(50mg, 0.16 mmol), NaHCO3 (1.1 mg,
d
168.8, 159.9, 158.4, 133.6, 133.5, 129.6, 129.3, 121.9, 120.4, 120.3,
114.0, 112.6, 110.6, 90.4, 89.3, 66.7, 61.1, 55.7, and 14.1; HRMS calcd
13
m
mol), MgSO4 (5 mg, 39
m
mol), NaIO4 (103 mg, 0.47 mmol), and
for [(C19H18O4)þNa]þ: 333.1097. Found: 333.1107.
a 0.01 M RuCl3 solution (160
m
L, 1.6 mol) were used. The reaction
m
mixture was stirred at room temperature for 2 h and then worked up
to obtain the title compound 1c (44 mg, 78% yield) as a pale yellow oil,
which was pure to use for next step without further purification; IR
(neat) 2925,1733,1597,1458,1199, and 1074 cmꢁ1;1HNMR (300 MHz,
4.7. Ethyl-2-(2-ethynylphenoxy)acetate (6u)32b
To a stirred solution of compound 6t (50 mg, 0.16 mmol) in THF
(6 mL) at 0 ꢀC was added tetra-n-butyl-ammonium fluoride (TBAF)
(74 mg, 0.16 mmol) in THF (2 mL). After 10 min at 0 ꢀC, the reaction
mixture was hydrolyzed with a saturated aqueous solution of
NH4Cl and extracted with Et2O. The combined organic extracts
were washed with brine, dried over MgSO4, and concentrated un-
der reduced pressure to afford the title compound 6u (25 mg, 68%
yield) as a pale yellow oil, which was pure to use in the next step
without further purification; IR (neat) 3280, 2924, 1756, 1489, and
CDCl3)
d
1.30 (t, 3H, J¼7.1 Hz), 1.49e1.79 (m, 6H), 3.52 (d, 1H,
J¼11.3 Hz), 3.83(t,1H, J¼9.4and10.9 Hz), 4.27 (q, 2H, J¼7.1 Hz), 4.65 (s,
2H), 4.77 (m, 3H), 6.88 (d, 1H, J¼8.3 Hz), 7.15 (t, 1H, J¼7.5 Hz), 7.57 (t,
1H, J¼8.3 Hz), and 7.88 (d, 1H, J¼7.5 Hz); 13C NMR (75 MHz, CDCl3)
d
200.2, 194.3, 167.6, 158.4, 136.0, 130.5, 123.9, 122.5, 112.9, 98.4, 68.6,
66.1, 61.8, 61.6, 30.0, 25.3,18.7, and 14.1; HRMS calcd for [(C18H22O7)þ
Na]þ: 373.1258. Found: 373.1254.
1199 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
1.28 (t, 3H, J¼7.1 Hz), 3.32
4.8.4. Ethyl-2-(5-methoxy-2-(2-oxo-2-phenylacetyl)phenoxy) ace-
(s,1H), 4.26 (q, 2H, J¼7.1 Hz), 4.73 (s, 2H), 6.78 (d,1H, J¼8.1 Hz), 6.96
(td, 1H, J¼7.6 and 0.9 Hz), 7.29 (td, 1H, J¼8.1 and 1.7 Hz), and 7.48
tate (1d). Alkyne 6d (260 mg, 0.84 mmol), NaHCO3 (5 mg, 67
MgSO4 (26 mg, 0.21 mmol), NaIO4 (545 mg, 2.51 mmol), and
a 0.01 M RuCl3 solution (850 L, 8 mol) were used. The reaction
mmol),
(dd, 1H, J¼7.6 and 1.7 Hz); 13C NMR (75 MHz, CDCl3)
d
168.6, 134.4,
m
m
130.1, 121.6, 112.5, 81.6, 79.6, 66.1, 61.4, 29.7 and 14.1; HRMS calcd
mixture was stirred for 1 h. Purification by column chromatography
(SiO2, 10% EtOAc/hexane) provided the title compound 1d (235 mg,
81% yield) as a yellow solid; mp 81e82 ꢀC; IR (neat) 2924, 1756,
for [(C12H12O3)þH]þ: 205.0786. Found: 205.0789.
4.8. General procedure for oxidation of alkynes to 1,2-
diketones
1679, 1595, and 1166 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 1.10 (t, 3H,
J¼7.1 Hz), 3.78 (s, 3H), 4.01 (q, 2H, J¼7.1 Hz), 4.30 (s, 2H), 6.29 (s,
1H), 6.65 (d, 1H, J¼8.8 Hz), 7.42 (t, 2H, J¼7.4 Hz), 7.54 (t, 1H,
J¼7.2 Hz), 7.87 (d, 2H, J¼7.4 Hz), and 7.99 (d, 1H, J¼8.8 Hz); 13C NMR
To a solution of the alkyne substrate (1.0 equiv), NaHCO3
(0.08 equiv), MgSO4 (0.25 equiv), and NaIO4 (3.0 equiv) in a mixture
of 3:3:4 of MeCN/CCl4/H2O (5 mL/mmol of substrate) was added
(0.01 equiv) of a 0.01 M stock solution of RuCl3 in water. The re-
action mixture was stirred at room temperature until completion
and then extracted with EtOAc two times. The combined organic
layer was washed with H2O and brine, dried over NaSO4 (s), and
concentrated. Unless otherwise noted, the crude residue was pu-
rified to obtain the title compound as pure product.
(75 MHz, CDCl3)
d 193.3, 192.7, 166.9, 166.2, 160.2, 133.3, 132.7,
132.3, 129.1, 128.2, 117.1,107.6, 98.9, 65.3, 60.9, 55.4, and 13.6; HRMS
calcd for [(C19H18O6)þH]þ: 343.1176. Found: 343.1166.
4.8.5. Ethyl-2-(5-methoxy-2-(2-(4-methoxyphenyl)-2-oxoacetyl)
phenoxy)acetate (1e). Alkyne 6e (200 mg, 0.59 mmol), NaHCO3
(4 mg, 47
mmol), MgSO4 (18 mg, 0.15 mmol), NaIO4 (379 mg,
1.76 mmol), and a 0.01 M RuCl3 solution (600
m
L, 6 mol) were used.
m
The reaction mixture was stirred for 1 h. Purification by column
chromatography (SiO2, 20% EtOAc/hexane) provided the title
compound 1e (208 mg, 95% yield) as a colorless solid; mp
4.8.1. Ethyl-2-(2-(2-oxo-2-phenylacetyl)phenoxy)acetate
(1a). Alkyne 6a (103 mg, 0.37 mmol), NaHCO3 (3 mg, 29
MgSO4 (11 mg, 92 mol), NaIO4 (237 mg, 1.10 mmol), and a 0.01 M
RuCl3 solution (370 L, 4 mol) were used. The reaction mixture
mmol),
m
117e118 ꢀC; IR (neat) 2923, 1755, 1663, 1595, and 1165 cmꢁ1 1H
;
m
m
NMR (300 MHz, CDCl3)
d
1.09 (t, 3H, J¼7.0 Hz), 3.75 (s, 3H), 3.77 (s,
was stirred for 30 min. Purification by column chromatography
(SiO2, 20% EtOAc/hexane) provided the title compound 1a (109 mg,
95% yield) as pale a yellow oil; IR (neat) 2976, 1755, 1681, 1598, and
3H), 4.01 (q, 2H, J¼7.0 Hz), 4.29 (s, 2H), 6.23 (s, 1H), 6.60 (d, 1H,
J¼8.7 Hz), 6.86 (d, 2H, J¼8.3 Hz), 7.80 (d, 2H, J¼8.3 Hz), and 7.94 (d,
1H, J¼8.7 Hz); 13C NMR (75 MHz, CDCl3)
d 193.3, 192.6, 167.5, 166.4,
1199 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
1.16 (t, 3H, J¼7.1 Hz), 4.07
164.1, 160.6, 132.8, 131.9, 126.1, 117.9, 113.9, 107.9, 99.6, 66.0, 61.4,
55.8, 55.5, and 14.0; HRMS calcd for [(C20H20O7)þH]þ: 373.1282.
Found: 373.1281.
(q, 2H, J¼7.1 Hz), 4.39 (s, 2H), 6.85 (d, 1H, J¼8.4 Hz), 7.19 (t, 1H,
J¼7.6 Hz), 7.49 (t, 2H, J¼7.6 Hz), 7.59 (t, 1H, J¼7.6 Hz), 7.61 (t, 1H,
J¼8.1 Hz), 7.95 (d, 2H, J¼8.1 Hz), and 8.05 (d, 1H, J¼7.6 Hz); 13C NMR
(75 MHz, CDCl3)
d
194.3,193.1,167.5,158.6, 136.2,133.9,132.8,130.9,
4.8.6. Ethyl-2-(4-methoxy-2-(2-oxohexanoyl)phenoxy)acetate
129.7, 128.6, 124.5, 122.6, 113.2, 65.9, 61.4, and 14.0; HRMS calcd for
(1f). Alkyne 6f (30 mg, 0.10 mmol), NaHCO3 (0.7 mg, 8
MgSO4 (3.1 mg, 26 mol), NaIO4 (66 mg, 0.31 mmol), and 0.01 M
RuCl3 (104 L, 1 mol) were used. The reaction mixture was stirred
mmol),
[(C18H16O5)þH]þ: 313.1071. Found: 313.1080.
m
m
m
4.8.2. Ethyl-2-(2-(2-oxohexanoyl)phenoxy)acetate (1b). Alkyne 6b
(739 mg, 2.84 mmol), NaHCO3 (19 mg, 0.23 mmol), MgSO4 (85 mg,
0.71 mmol), NaIO4 (1.8 g, 8.52 mmol), and a 0.01 M RuCl3 solution
at room temperature for 30 min and then worked up to obtain the
title compound 6f (16 mg, 48% yield) as a pale yellow oil; IR (neat)
2929, 1758, 1714, 1664, 1493, 1193, and 1063 cmꢁ1 1H NMR
;
(2.8 mL, 28
m
mol) were used. The reaction mixture was stirred for
(300 MHz, CDCl3)
d
0.95 (t, 3H, J¼7.4 Hz), 1.29 (t, 3H, J¼7.1 Hz), 1.40
2 h. Purification by column chromatography (SiO2, 20% EtOAc/
hexane) provided the title compound 1b (539 mg, 65% yield) as
a pale yellow oil; IR (neat) 2960, 1760, 1667, 1598, 1200, and
(sext, 2H, J¼7.4 Hz), 1.68 (pent, 2H, J¼7.4 Hz), 2.88 (t, 2H, J¼7.4 Hz),
3.81 (s, 3H), 4.25 (q, 2H, J¼7.1 Hz), 4.52 (s, 2H), 6.86 (d, 1H,
J¼9.1 Hz), 7.11 (dd, 1H, J¼9.1 and 3.2 Hz), and 7.33 (t, 1H, J¼3.2 Hz);

9344
S. Bensulong et al. / Tetrahedron 69 (2013) 9335e9348
13C NMR (75 MHz, CDCl3)
d
203.2, 194.5, 167.9, 154.9, 152.6, 124.6,
55.5, and 14.0; HRMS calcd for [(C19H18O6)þH]þ : 343.1176. Found:
122.9, 115.3, 113.0, 66.9, 61.4, 55.8, 31.1, 24.6, 22.2, 14.0, and 13.8;
343.1183.
HRMS calcd for [(C17H22O6)þH]þ: 323.1485. Found: 323.1489.
4.8.11. Ethyl-2-(2-(2-(3,4-dimethoxyphenyl)-2-oxoacetyl) phenoxy)
acetate (1k). Alkyne 6k (800 mg, 2.35 mmol), NaHCO3 (16 mg,
0.19 mmol), MgSO4 (71 mg, 0.59 mmol), NaIO4 (1.51 g, 7.06 mmol),
4.8.7. Ethyl-2-(2-(2-oxo-2-phenylacetyl)-5-(tosyloxy)phenoxy) ace-
tate (1g). Alkyne 6g (55 mg, 0.12 mmol), NaHCO3 (1 mg, 10
MgSO4 (4 mg, 30 mol), NaIO4 (73 mg, 0.37 mmol), and RuCl3
(122 L,1 mol) were used. The reaction mixture was stirred for 1 h.
mmol),
m
and RuCl3 (2.4 mL, 24 mmol) were used. The reaction mixture was
m
m
stirred for 1 h and the crude product was purified by column chro-
matography (SiO2, 20% EtOAc/hexane) to furnish the title compound
1k (653 mg, 75% yield) as a bright yellow solid; IR (neat) 2939, 1755,
Purification by preparative thin layer chromatography (SiO2, 20%
EtOAc/hexane) provided the title 1g (36 mg, 63% yield) as a yellow
oil; IR (neat) 2983,1756, 1678, 1597, 1377, 1192, 1090, and 954 cmꢁ1
;
1662, 1596, 1265, 1195, and 1020 cmꢁ1 1H NMR (300 MHz, CDCl3)
;
1H NMR (300 MHz, CDCl3)
d
1.27 (t, 3H, J¼7.1 Hz), 2.46 (s, 3H), 4.07
d
1.18 (t, 3H, J¼6.9 Hz), 3.94 (s, 6H), 4.09 (q, 2H, J¼6.9 Hz), 4.42 (s, 2H),
(q, 2H, J¼7.1 Hz), 4.32 (s, 2H), 6.65 (s,1H), 6.68 (d,1H, J¼8.7 Hz), 7.35
(d, 2H, J¼8.0 Hz), 7.48 (d, 1H, J¼7.4 Hz), 7.51 (d, 1H, J¼7.6 Hz), 7.62
(dd, 1H, J¼7.6 and 7.4 Hz), 7.73 (d, 2H, J¼8.0 Hz), and 7.89e7.98 (m,
6.85 (d, 1H, J¼8.4 Hz), 6.90 (d, 1H, J¼8.4 Hz), 7.17 (t, 1H, J¼7.5 Hz),
7.48e7.48 (m, 3H), 8.01 (d, 1H, J¼7.5 Hz); 13C NMR (75 MHz, CDCl3)
d
194.2, 192.0, 167.5, 158.5, 153.9, 149.1, 135.9, 130.8, 125.8, 125.4,
3H); 13C NMR (75 MHz, CDCl3)
d
193.0, 192.6, 166.7, 159.3, 155.1,
124.7, 122.4, 113.2, 110.6, 110.2, 65.9, 61.3, 56.0, 55.9, and 13.9; HRMS
146.0, 134.1, 132.5, 132.2, 131.8,130.0, 129.7, 128.7,128.5, 123.0, 116.1,
107.8, 65.8, 61.6, 21.7, and 13.9; HRMS calcd for [(C25H22O8S)þNa]þ:
505.0928. Found: 505.0920.
calcd for [(C20H20O7)þNa]þ: 395.1101. Found: 395.1090.
4.8.12. Ethyl-3-(2-ethoxy-2-oxoethoxy)-4-(2-oxo-2-phenylacetyl)
benzoate (1l). Alkyne 6l (214 mg, 0.61 mmol), NaHCO3 (4 mg,
4.8.8. Ethyl-2-(2-(2-(3,4-dimethoxyphenyl)-2-oxoacetyl)-5-(tosy-
loxy)phenoxy)acetate (1h). Alkyne 6h (1.20 g, 2.35 mmol), NaHCO3
(16 mg, 0.2 mmol), MgSO4 (71 mg, 0.6 mmol), NaIO4 (1.5 g,
49
m
mol), MgSO4 (18 mg, 0.15 mmol), NaIO4 (391 mg,1.82 mmol), and
a 0.01 M RuCl3 solution (610
m
L, 6 mol) were used. The reaction
m
mixture was stirred for 2 h. Purification by column chromatography
(SiO2, 20% EtOAc/hexane) provided the title compound 1l (198 mg,
85% yield) as a yellow oil; IR (neat) 2983, 1721, 1678, 1420, and
7.05 mmol), and 0.01 M RuCl3 (2.4 mL, 24 mmol) were used. The
reaction mixture was stirred for 1 h. Purification by column chro-
matography (SiO2, 30% EtOAc/hexane) provided the title compound
1h (1.0 g, 81% yield) as a pale yellow oil; IR (neat) 2973, 1754, 1663,
1196 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
1.05 (t, 3H, J¼6.9 Hz), 1.29 (t,
3H, J¼6.9 Hz), 3.96 (q, 2H, J¼6.9 Hz), 4.29 (q, 2H, J¼6.9 Hz), 4.37 (s,
2H), 7.40 (t, 3H, J¼10.7 and 7.2 Hz), 7.52 (t, 1H, J¼6.9 Hz), 7.73 (d, 1H,
J¼7.8 Hz), 7.85 (d, 2H, J¼7.2 Hz), and 7.95 (d, 1H, J¼7.8 Hz); 13C NMR
1596, 1261, 1192, and 1019 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 1.20
(t, 3H, J¼7.2 Hz), 2.46 (s, 3H), 3.95 (s, 6H), 4.11 (q, 2H, J¼7.2 Hz), 4.36
(s, 2H), 6.66 (s,1H), 6.69 (d,1H, J¼8.2 Hz), 6.91 (d,1H, J¼8.2 Hz), 7.34
(d, 2H, J¼7.7 Hz), 7.46 (d, 1H, J¼8.2 Hz), 7.54 (s, 1H), 7.73 (d, 2H,
J¼7.7 Hz), and 7.92 (d, 1H, J¼8.2 Hz); 13C NMR (75 MHz, CDCl3)
(75 MHz, CDCl3)
d 192.7, 191.4, 166.1, 164.0, 157.1, 136.0, 133.1, 131.5,
129.9, 128.7, 127.7, 126.8, 122.2, 113.0, 64.7, 60.7, 60.4, 13.2, and 12.9;
HRMS calcd for [(C21H20O7)þNa]þ: 407.1101. Found: 407.1106.
d
192.2, 191.6, 166.8, 159.2, 154.9, 154.2, 149.2, 146.0, 132.3, 131.8,
130.0, 128.5, 125.6, 125.5, 123.3, 116.0, 110.6, 110.2, 107.9, 65.9, 61.6,
56.1, 56.0, 21.7, and 14.0; HRMS calcd for [(C27H26O10S)þH]þ:
543.1319. Found: 543.1314.
4.8.13. Ethyl-2-(2-(3,3-dimethyl-2-oxobutanoyl)phenoxy)acetate
(1m). Alkyne 6m (100 mg, 0.38 mmol), NaHCO3 (3 mg, 31
MgSO4 (11 mg, 96 mol), NaIO4 (244 mg, 1.15 mmol), and a 0.01 M
RuCl3 solution (400 L, 4 mol) were used. The reaction mixture
mmol),
m
m
m
4.8.9. Ethyl-2-(2-(2-(2-methoxyphenyl)-2-oxoacetyl)phenoxy) ace-
was stirred for 1 h. Purification by column chromatography (SiO2,
15% EtOAc/hexane) provided the title compound 1m (45 mg, 91%
yield) as a pale yellow oil; IR (neat) 2967, 2927,1756,1597,1458, and
tate (1i). Alkyne 6i (30 mg, 97
MgSO4 (3 mg, 25 mol), NaIO4 (64 mg, 0.29 mmol), and a 0.01 M
RuCl3 solution (100 L, 1 mol) were used. The reaction mixture
mmol), NaHCO3 (0.6 mg, 8 mmol),
m
m
m
1194 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
1.28 (t, 3H, J¼7.1 Hz), 1.33
was stirred for 1 h and the crude product was purified by pre-
parative thin layer chromatography (SiO2, 20% EtOAc/hexane) to
furnish the title compound 1i (28 mg, 87% yield) as a pale yellow
oil; IR (neat) 2937, 1756, 1658, 1596, 1484, and 1279 cmꢁ1; 1H NMR
(s, 9H), 4.26 (q, 2H, J¼7.1 Hz), 4.62 (s, 2H), 6.83 (d, 1H, J¼8.2 Hz), 7.14
(t, 1H, J¼7.5 and 8.2 Hz), 7.55 (t, 1H, J¼7.5 and 8.2 Hz), and 7.94 (d,
1H, J¼7.5 Hz); 13C NMR (75 MHz, CDCl3)
d 209.4, 194.7, 167.9, 158.2,
135.9, 130.6, 122.4, 121.8, 112.8, 66.0, 61.6, 42.0, 26.5, and 14.0;
(300 MHz, CDCl3)
d
1.16 (t, 3H, J¼7.1 Hz), 3.62 (s, 3H), 4.06 (q, 2H,
HRMS calcd for [(C16H20O5)þH]þ: 293.1384. Found: 293.1383.
J¼7.1 Hz), 4.40 (s, 2H), 6.85 (d, 1H, J¼8.3 Hz), 6.95 (d, 1H, J¼8.3 Hz),
7.10 (t,1H, J¼8.3 Hz), 7.18 (t,1H, J¼7.6 Hz), 7.56 (br s, 2H), 8.05 (d,1H,
J¼7.6 Hz), and 8.12 (d, 1H, J¼7.6 Hz); 13C NMR (75 MHz, CDCl3)
4.8.14. Ethyl-2-(2-(2-(3,4-dimethoxyphenyl)-2-oxoacetyl)-3,5-
dimethoxyphenoxy)acetate (1n). Alkyne 6n (1.38 g, 3.5 mmol),
NaHCO3 (23 mg, 0.28 mmol), MgSO4 (104 mg, 0.86 mmol), NaIO4
d
192.3, 191.9, 167.7, 160.5, 158.6, 135.6, 135.3, 130.8, 130.5, 123.8,
123.5, 122.3, 121.1, 112.4, 66.2, 61.3, 55.8, and 14.0; HRMS calcd for
(2.2 g, 10.35 mmol), and 0.01 M RuCl3 solution (3.5 mL, 35 mmol)
[(C19H18O6)þNa]þ: 365.0996. Found: 365.0989.
were used. The reaction mixture was stirred for 30 h. Purification by
column chromatography (SiO2, 15% EtOAc/hexane) provided the
title compound 1n (988 mg, 67% yield) as a pale yellow solid; mp
118e120 ꢀC; IR (neat) 2940, 2843, 1754, 1613, 1598, 1580, 1131, and
4.8.10. Ethyl-2-(2-(2-(4-methoxyphenyl)-2-oxoacetyl)phenoxy) ace-
tate (1j). Alkyne 6j (26 mg, 84
m
mol), NaHCO3 (0.6 mg, 7
mol), NaIO4 (85 mg, 0.25 mmol), and a 0.01 M
L, 1 mol) were used. The reaction mixture was
mmol),
MgSO4 (3 mg, 21
m
1020 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
1.24 (t, 3H, J¼7.1 Hz), 3.70
RuCl3 solution (90
m
m
(s, 3H), 3.82 (s, 3H), 3.93 (s, 3H), 3.95 (s, 3H), 4.17 (q, 2H, J¼7.1 Hz),
4.51 (s, 2H), 6.02 (s, 1H), 6.15 (s, 1H), 6.92 (d, 1H, J¼8.4 Hz), and 7.59
stirred for 1 h and the crude product was purified by preparative
thin layer chromatography (SiO2, 20% EtOAc/hexane) to furnish the
title compound 1j (29 mg, 94% yield) as a pale yellow oil; IR (neat)
2924, 1756, 1666, 1596, and 1258 cmꢁ1; 1H NMR (300 MHz, CDCl3)
(d, 2H, J¼8.4 Hz); 13C NMR (75 MHz, CDCl3)
d 191.6, 190.8, 167.8,
165.5, 162.9, 161.0, 153.3, 148.7, 126.0, 125.1, 111.1, 110.1, 108.6, 92.5,
91.9, 66.2, 61.3, 55.9, 55.8 (ꢂ2), 55.5, and 13.9; HRMS calcd for
[(C22H24O9)þNa]þ: 455.1312. Found: 455.1306.
d
1.18 (t, 3H, J¼7.1 Hz), 3.88 (s, 3H), 4.10 (q, 2H, J¼7.1 Hz), 4.41 (s,
2H), 6.85 (d, 1H, J¼8.5 Hz), 6.97 (d, 2H, J¼8.5 Hz), 7.18 (t, 1H,
J¼7.5 Hz), 7.57 (t, 1H, J¼7.7 Hz), 7.93 (d, 2H, J¼8.5 Hz), and 8.02 (d,
4.8.15. Ethyl-2-(2-(2-(4-nitrophenyl)-2-oxoacetyl)phenoxy)acetate
1H, J¼7.7 Hz); 13C NMR (75 MHz, CDCl3)
d
194.5, 192.0, 167.7, 164.2,
(1o). Alkyne 6o (20 mg, 61
mmol), NaHCO3 (0.4 mg, 5 mmol), MgSO4
158.6, 136.0, 132.1, 131.0, 125.8, 124.8, 122.6, 114.0, 113.3, 66.0, 61.4,
(2 mg, 15 mol), NaIO4 (39 mg, 0.18 mmol), and a 0.01 M RuCl3
m

S. Bensulong et al. / Tetrahedron 69 (2013) 9335e9348
9345
solution (60
m
L, 1
m
mol) were used. The reaction mixture was stir-
4.9.1. Ethyl-4-oxo-3-phenyl-4H-chromene-2-carboxylate (2a)33 and
ethyl-3-benzoylbenzofuran-2-carboxylate (3a). The diketone 1a
(320 mg, 1.02 mmol) and DBU (200 mL, 1.13 mmol) were used. The
red for 1 h and then worked up to obtain the title compound 1o
(19 mg, 86% yield) as a yellow oil, which was used for next step
without further purification; IR (neat) 2923, 1756, 1598, and
reaction mixture was heated for 1 h. Purification by preparative
thin layer chromatography (SiO2, 20% EtOAc/hexane) provided the
title compound 2a (253 mg, 84% yield) as a white solid and com-
pound 3a (19 mg, 3% yield) as a pale yellow solid; 2a: mp 86e88 ꢀC;
1200 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
1.18 (t, 3H, J¼7.0 Hz), 4.09
(q, 2H, J¼7.0 Hz), 4.41 (s, 2H), 6.86 (d, 1H, J¼8.4 Hz), 7.23 (t, 1H,
J¼7.8 Hz), 7.63 (t, 1H, J¼7.8 Hz), 8.05 (d, 1H, J¼7.8 Hz), 8.14 (d, 2H,
J¼8.0 Hz), and 8.34 (d, 2H, J¼8.0 Hz); 13C NMR (75 MHz, CDCl3)
IR (neat) 2983, 1736, 1650, 1617, 1465, and 1296 cmꢁ1 1H NMR
;
d
193.3, 190.8, 167.0, 158.5, 150.7, 137.5, 136.7, 131.0, 130.8, 123.9,
(300 MHz, CDCl3)
d
0.98 (t, 3H, J¼7.1 Hz), 4.15 (q, 2H, J¼7.1 Hz),
123.8, 122.8, 112.9, 65.6, 61.6, and 14.0; HRMS calcd for
7.29e7.32 (m, 2H), 7.37e7.46 (m, 4H), 7.56 (d, 1H, J¼8.5 Hz), 7.75 (t,
[(C18H15NO7)þH]þ: 358.0921. Found: 358.0919.
1H, J¼7.8 Hz), 8.25 (d, 1H, J¼7.8 Hz); 13C NMR (75 MHz, CDCl3)
d
177.2, 161.6, 155.4, 150.8, 134.4, 131.2, 129.6, 128.3, 128.0, 126.2,
4.8.16. Ethyl-2-(5-methoxy-2-(2-(4-nitrophenyl)-2-oxoacetyl) phe-
noxy)acetate (1p). Alkyne 6p (173 mg, 0.49 mmol), NaHCO3 (3 mg,
125.8, 125.6, 123.6, 118.3, 62.3, and 13.3. HRMS calcd for
[(C18H14O4)þNa]þ: 317.0784. Found: 317.0783.
39
mmol), MgSO4 (1 mg, 0.12 mmol), NaIO4 (314 mg, 1.46 mmol),
Compound 3a: mp 85e86 ꢀC; IR (neat) 2924, 1729, 1659, 1579,
and a 0.01 M RuCl3 solution (490
m
L, 5 mol) were used. The re-
m
1299, and 1147 cmꢁ1 1H NMR (300 MHz, CDCl3)
; d 1.00 (t, 3H,
action mixture was stirred for 2 h. Purification by column chro-
matography (SiO2, 20% EtOAc/hexane) provided the title compound
1p (158 mg, 83% yield) as a yellow solid; mp 151e153 ꢀC; IR (neat)
J¼7.1 Hz), 4.17 (q, 2H, J¼7.1 Hz), 7.34 (t, 1H, J¼7.3 Hz), 7.45e7.68 (m,
6H), and 7.92 (d, 2H, J¼7.5 Hz); 13C NMR (75 MHz, CDCl3)
d 190.7,
158.6, 154.6, 137.4, 134.8, 133.8, 129.4, 128.7, 128.4, 125.7, 124.6,
123.9,122.1,112.4, 61.9, and 13.5. HRMS calcd for [(C18H14O4)þNa]þ:
317.0784. Found: 317.0788.
2923, 1760, 1686, 1592, 1526, and 1210 cmꢁ1 1H NMR (300 MHz,
;
CDCl3)
d
1.18 (t, 3H, J¼7.1 Hz), 3.89 (s, 3H), 4.09 (q, 2H, J¼7.1 Hz),
4.38 (s, 2H), 6.30 (s, 1H), 6.74 (d, 1H, J¼8.7 Hz), 8.08 (d, 1H,
J¼8.7 Hz), 8.11 (d, 2H, J¼8.4 Hz), and 8.32 (d, 2H, J¼8.4 Hz); 13C NMR
4.9.2. Ethyl-3-butyl-4-oxo-4H-chromene-2-carboxylate
(2b). The
(75 MHz, CDCl3)
d
191.9, 191.4, 167.0, 166.8, 160.5, 150.6, 137.8, 133.0,
diketone 1b (100 mg, 0.34 mmol) and DBU (71 L, 0.38 mmol) were
m
130.6, 123.7, 117.1, 108.0, 99.3, 65.6, 61.6, 55.9, and 14.0; HRMS calcd
used. The reaction mixture was heated for 1 h. Purification by pre-
parative thin layer chromatography (SiO2, 20% EtOAc/hexane) pro-
vided thetitle compound2b (69mg, 74%yield)as apaleyellowoil;IR
for [(C19H17NO8)þH]þ: 388.1027. Found: 388.1012.
4.8.17. Ethyl-2-(5-nitro-2-(2-oxo-2-phenylacetyl)phenoxy)acetate
(neat) 2958, 2927, 1734, 1647, 1617, 1467, 1294, and 1414 cmꢁ1 1H
;
(1q). Alkyne 6q (140 mg, 0.43 mmol), NaHCO3 (3 mg, 34
MgSO4 (14 mg, 0.11 mmol), NaIO4 (289 mg, 1.29 mmol), and a 0.01 M
RuCl3 solution (450 L, 4 mol) were used. Purification by preparative
m
mol),
NMR (300 MHz, CDCl3)
d
0.95 (t, 3H, J¼7.1 Hz),1.35e1.61 (m, 4H),1.48
(t, 3H, J¼7.1 Hz), 2.85 (t, 2H, J¼7.1 Hz), 4.48 (t, 2H, J¼7.1 Hz), 7.39 (t,
1H, J¼7.6 Hz), 7.51 (d,1H, J¼7.6 Hz), 7.70 (t,1H, J¼7.6 Hz), and 8.18 (d,
m
m
thin layer chromatography (SiO2, 20% EtOAc/hexane) provided the
1H, J¼7.6 Hz); 13C NMR (75 MHz, CDCl3)
d 178.4, 161.6, 155.3, 149.1,
title compound 1q (134 mg, 83% yield) as a yellow oil; IR (neat) 2927,
134.1, 128.0, 125.9, 125.2, 122.8, 118.2, 62.4, 31.4, 24.2, 22.9, 14.1, and
1754, 1679, 1532, and 1199 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
1.18 (t,
13.8; HRMS calcd for [(C16H18O4)þNa]þ: 297.1097. Found: 297.1089.
3H, J¼7.0 Hz), 4.10 (q, 2H, J¼7.0 Hz), 4.52 (s, 2H), 7.52 (t, 2H, J¼7.5 Hz),
7.66 (t, 1H, J¼7.2 Hz), 7.71 (s,1H), 7.98 (dd, 3H, J¼14.4 and 7.5 Hz), and
4.9.3. Ethyl-4-oxo-3-((tetrahydro-2H-pyran-2-yloxy)methyl)-4H-
chromene-2-carboxylate (2c). The diketone 1c (43 mg, 0.12 mmol)
and DBU (25 mL, 0.13 mmol) were used. The reaction mixture was
8.14 (d, 1H, J¼8.4 Hz); 13C NMR (75 MHz, CDCl3)
d
192.5, 191.6, 166.5,
158.2,151.9,134.4,132.0,129.8,129.5,128.8,117.1,108.3, 65.9, 61.8, and
13.9; HRMS calcd for [(C18H15NO7)þH]þ: 358.0921. Found: 358.0925.
heated for 2 h. Purification by preparative thin layer chromatog-
raphy (SiO2, 30% EtOAc/hexane) provided the title compound 2c
(29 mg, 73% yield) as a pale yellow oil; IR (neat) 2942, 1740, 1652,
4.8.18. Ethyl-2-(2-(2-(4-methoxyphenyl)-2-oxoacetyl)-5-nitro phe-
noxy)acetate (1r). Alkyne 6r (495 mg, 1.39 mmol), NaHCO3 (9 mg,
0.11 mmol), MgSO4 (42 mg, 0.35 mmol), NaIO4 (892 mg, 4.17 mmol),
1467, 1239, and 1025 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 1.43e1.84
(m, 9H), 3.53e3.61 (m, 1H), 3.92 (t, 1H, J¼10.2 Hz), 4.48 (q, 2H,
J¼7.1 Hz), 4.71 (d, 1H, J¼11.1 Hz), 4.81 (br s, 1H), 5.01 (d, 1H,
J¼11.1 Hz), 7.44 (t, 1H, J¼7.8 Hz), 7.53 (dd,1H, J¼8.0 and 0.4 Hz), 7.72
(t, 1H, J¼7.8 Hz), and 8.22 (d, 1H, J¼8.0 Hz); 13C NMR (100 MHz,
and a 0.01 M RuCl3 solution (1.4mL,14 mmol) wereused. Thereaction
mixture was stirred for 2 h. Purification by column chromatography
(SiO2, 20% EtOAc/hexane) provided the title compound 1r (480 mg,
89% yield) as a yellow oil; IR (neat) 2926, 1753,1671, 1598,1532, and
CDCl3)
d 177.5, 161.2, 155.4, 134.3, 126.0, 125.6, 123.4, 122.1, 118.3,
1203 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
1.21 (t, 3H, J¼7.1 Hz), 3.90 (s,
116.5, 98.9, 62.7, 61.8, 58.6, 30.4, 25.4, 19.1, and 13.9; HRMS calcd for
3H), 4.14 (q, 2H, J¼7.1 Hz), 4.53 (s, 2H), 7.00 (d, 2H, J¼8.6 Hz), 7.70 (s,
[(C18H20O6)þH]þ: 355.1152. Found: 355.1161.
1H), 7.96 (d, 2H, J¼8.6 Hz), 8.02 (d, 1H, J¼8.5 Hz), and 8.12 (d, 1H,
J¼8.5 Hz); 13C NMR (75 MHz, CDCl3)
d
192.6,190.4,166.7,164.7,158.3,
4.9.4. Ethyl-7-methoxy-4-oxo-3-phenyl-4H-chromene-2-carboxylate
(2d). The diketone 1d (180 mg, 0.53 mmol) and DBU (110 mL,
151.9,132.4,132.2,130.1,125.1,117.2,114.2,108.5, 66.2, 61.9, 55.6 and
14.0; HRMS calcd for [(C19H17NO8)þH]þ: 388.1027. Found: 388.1036.
0.58 mmol) were used. The reaction mixture was heated for 1 h.
Purification by preparative thin layer chromatography (SiO2, 20%
EtOAc/hexane) provided the title compound 2d (136 mg, 78% yield)
as a yellow solid; mp 130e132 ꢀC; IR (neat) 2977, 1735, 1621, 1438,
4.9. Procedure for DBU-induced cyclization reaction
and 1250 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
0.97 (t, 3H, J¼7.1 Hz),
To a solution of the diketone 1 (1.0 equiv) in DMSO (5 mL/mmol
of substrate) was added 1.1 equiv of diazabicycloundecene (DBU)
dropwise. The reaction mixture was heated at 100 ꢀC until com-
pletion as indicated by TLC. The reaction mixture was quenched
with a saturated NH4Cl solution and extracted three times with
EtOAc. The combined organic phase was washed with brine, dried
over Na2SO4, and concentrated under reduce pressure. After the
organic solvent was removed the crude residue was purified to
obtain the pure product.
3.91 (s, 3H), 4.12 (q, 2H, J¼7.1 Hz), 6.96 (d, 1H, J¼2.3 Hz), 7.01 (dd,
1H, J¼8.8 and 2.3 Hz), 7.28e7.30 (m, 2H), 7.38e7.44 (m, 3H), and
8.13 (d, 1H, J¼8.8 Hz); 13C NMR (100 MHz, CDCl3)
d 176.5, 164.7,
161.7, 157.3, 150.4, 131.5, 129.7, 128.2, 128.0, 127.6, 126.1, 117.6, 115.4,
100.2, 62.3, 55.9, and 13.3; HRMS calcd for [(C19H16O5)þH]þ:
325.1071. Found: 325.1062.
4.9.5. Ethyl-7-methoxy-3-(4-methoxyphenyl)-4-oxo-4H-chromene-
2-carboxylate (2e). The diketone 1e (88 mg, 0.23 mmol) and DBU

9346
S. Bensulong et al. / Tetrahedron 69 (2013) 9335e9348
(50
m
L, 0.26 mmol) were used. The reaction mixture was heated for
150.9, 134.3, 131.1, 129.8, 126.3, 125.5, 123.7, 123.2, 120.9, 120.4,
118.4, 110.7, 62.1, 55.6, and 13.5; HRMS calcd for [(C19H16O5)þNa]þ:
347.0889. Found: 347.0884.
1 h. Purification by preparative thin layer chromatography (SiO2,
20% EtOAc/hexane) provided the title compound 2e (57 mg, 70%
yield) as a colorless solid; mp 117e118 ꢀC; IR (neat) 2981, 1733,
1609, 1438, and 1246 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
1.06 (t, 3H,
4.9.10. Ethyl-3-(4-methoxyphenyl)-4-oxo-4H-chromene-2-
J¼7.1 Hz), 3.83 (s, 3H), 3.90 (s, 3H), 4.16 (q, 2H, J¼7.1 Hz), 6.93e7.00
carboxylate (2j) and ethyl-3-(4-methoxybenzoyl) benzofuran-2-
(m, 4H), 7.23 (d, 2H, J¼8.8 Hz), and 8.13 (d, 1H, J¼8.8 Hz); 13C NMR
carboxylate (3j). The diketone 1j (28 mg, 80
mmol) and DBU
(100 MHz, CDCl3)
d
176.6, 164.6, 161.9, 159.7, 157.3, 150.3, 131.0,
(17 L, 88 mol) were used. The reaction mixture was heated for
m
m
127.6, 125.6, 123.5, 117.6, 115.3, 113.6, 100.1, 62.2, 55.8, 55.2, and
1 h. Purification by preparative thin layer chromatography (SiO2,
25% EtOAc/hexane) provided the title compound 2j (15 mg, 57%
yield) as a pale colorless solid and compound 3j (4 mg, 13% yield) as
a pale yellow solid; 2j: mp 86e87 ꢀC; IR (neat) 2935, 2833, 1738,
13.5; HRMS calcd for [(C20H18O6)þH]þ: 355.1176. Found: 355.1173.
4.9.6. Ethyl-3-butyl-6-methoxy-4-oxo-4H-chromene-2-carboxylate
(2f). The diketone 1f (31 mg, 96
m
mol) and DBU (14
mL, 106
mmol)
1652, 1466, and 1247 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 1.07 (t, 3H,
were used. The reaction mixture was heated for 1 h. Purification by
preparative thin layer chromatography (SiO2, 15% EtOAc/hexane)
provided the title compound 2f (21 mg, 73% yield) as a pale yellow
oil; IR (neat) 2953, 1729, 1635, 1488, 1275, 1243, and 817 cmꢁ1; 1H
J¼7.1 Hz), 3.85 (s, 3H), 4.18 (q, 2H, J¼7.1 Hz), 6.97 (d, 2H, J¼8.7 Hz),
7.25 (d, 2H, J¼8.7 Hz), 7.45 (t, 1H, J¼8.0 Hz), 7.57 (d, 1H, J¼8.0 Hz),
7.74 (td, 1H, J¼8.0 and 1.6 Hz), and 8.26 (dd, 1H, J¼8.0 and 1.6 Hz);
13C NMR (100 MHz, CDCl3)
d 177.4, 161.9, 159.8, 155.5, 150.8, 134.3,
NMR (300 MHz, CDCl3)
d
0.95 (t, 3H, J¼7.1 Hz), 1.30e1.60 (m, 4H),
131.0, 126.3, 125.5, 125.3, 123.7, 123.3, 118.3, 113.7, 62.4, 55.2, and
13.5; HRMS calcd for [(C19H16O5)þH]þ: 325.1071. Found: 325.1071.
Compound 3j: mp 83e85 ꢀC; IR (neat) 2924, 1728, 1659, 1599,
1.45 (t, 3H, J¼7.1 Hz), 2.86 (t, 2H, J¼7.1 Hz), 3.90 (s, 3H), 4.46 (q, 2H,
J¼7.1 Hz), 7.29 (dd, 1H, J¼9.2 and 3.0 Hz), 7.45 (d, 1H, J¼9.2 Hz), and
7.53 (d, 1H, J¼3.0 Hz); 13C NMR (75 MHz, CDCl3)
d
178.2, 161.7, 157.0,
and 1247 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
1.07 (t, 3H, J¼7.1 Hz),
150.2, 149.0, 127.2, 124.6, 123.4, 119.8, 104.6, 62.4, 55.8, 31.5, 24.3,
22.9, 14.1, and 13.9; HRMS calcd for [(C17H20O5)þNa]þ: 327.1203
Found:327.1206.
3.88 (s, 3H), 4.22 (q, 2H, J¼7.1 Hz), 6.94 (d, 2H, J¼8.6 Hz), 7.32 (t, 1H,
J¼7.5 Hz), 7.50 (d, 1H, J¼7.5 Hz), 7.54 (t, 1H, J¼7.5 Hz), 7.66 (d, 1H,
J¼8.5 Hz), and 7.89 (d, 2H, J¼8.5 Hz); 13C NMR (151 MHz, CDCl3)
d
189.1, 164.3, 158.7, 154.7, 142.3, 131.9, 130.5, 128.3, 126.8, 126.3,
4.9.7. Ethyl-4-oxo-3-phenyl-7-(tosyloxy)-4H-chromene-2-
124.4, 122.1, 113.9, 112.4, 61.8, 55.6, and 13.7; HRMS calcd for
carboxylate (2g). The diketone 1g (35 mg, 73
mmol) and DBU (11
mL,
[(C19H16O5)þH]þ: 325.1071. Found: 325.1066.
79 mol) were used. The reaction mixture was heated for 1 h. Pu-
m
rification by preparative thin layer chromatography (SiO2, 15%
EtOAc/hexane) provided the title compound (18 mg, 56% yield) as
an off-white solid; mp 108e110 ꢀC; IR (neat) 2926, 1740, 1651, 1615,
4.9.11. Ethyl-3-(3,4-dimethoxyphenyl)-4-oxo-4H-chromene-2-
carboxylate (2k) and ethyl 3-(3,4-dimethoxybenzoyl)benzofuran-2-
carboxylate (3k). The diketone 1k (640 mg, 1.72 mmol) and DBU
(285 mL, 1.89 mmol) were used. The reaction mixture was heated
for 1 h. Purification by column chromatography (SiO2, 15% EtOAc/
hexane) provided the title compound 2k (322 mg, 53% yield) as
a pale yellow solid along with compound 3k (101 mg, 16% yield) as
an off-white solid; 2k; mp 138e140 ꢀC; IR (neat) 2937, 1734, 1650,
1258, 1222, 1117, and 1089 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 0.99
(t, 3H, J¼7.1 Hz), 2.47 (s, 3H), 4.13 (q, 2H, J¼7.1 Hz), 7.03 (d, 1H,
J¼8.7 Hz), 7.26 (br s, 2H), 7.31e7.45 (m, 6H), 7.76 (d, 2H, J¼8.1 Hz),
and 8.16 (d, 1H, J¼8.7 Hz); 13C NMR (75 MHz, CDCl3)
d 176.4, 161.3,
155.7,153.6, 151.2, 146.1,131.8,130.8, 130.1,129.6, 128.5, 128.4, 128.2,
128.1, 126.2, 122.3, 120.2, 112.2, 62.6, 21.7, 14.3; HRMS calcd for
[(C25H20O7S)þH]þ: 465.1003. Found: 465.0999.
1615, 1515, 1464, and 1299 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 0.98
(t, 3H, J¼7.0 Hz), 3.80 (s, 3H), 3.82 (s, 3H), 4.09 (q, 2H, J¼7.0 Hz), 6.76
(d, 1H, J¼8.2 Hz), 6.81 (s, 1H), 6.83 (d, 1H, J¼8.2 Hz), 7.34 (t, 1H,
J¼7.9 Hz), 7.47 (d, 1H, J¼7.9 Hz), 7.65 (t, 1H, J¼7.9 Hz), and 8.16 (d,
4.9.8. Ethyl-3-(3,4-dimethoxyphenyl)-4-oxo-7-(tosyloxy)-4H-chro-
mene-2-carboxylate (2h). The diketone 1h (75 mg, 0.14 mmol) and
1H, J¼7.9 Hz); 13C NMR (75 MHz, CDCl3)
d 177.3, 161.8, 155.3, 151.0,
DBU (23
mL, 0.15 mmol) were used. The reaction mixture was
149.2, 148.6, 134.3, 126.1, 125.5, 125.0, 123.6, 123.5, 122.2, 118.2,
113.0, 110.8, 62.3, 55.8 (ꢂ2), and 13.5; HRMS calcd for [(C20H18O6)þ
Na]þ: 377.0996. Found: 377.0988.
heated for 1 h. Purification by preparative thin layer chromatog-
raphy (SiO2, 25% EtOAc/hexane) provided the title compound
(41 mg, 56% yield) as a pale yellow solid; mp 126e128 ꢀC; IR (neat)
Compound 3k; mp 164e165 ꢀC; IR (neat) 2937, 1728, 1658, 1584,
2937, 1736, 1655, 1614, 1513, 1377, 1265, 1176, and 1021 cmꢁ1
;
1H
1301, 1273, 1262, 1174, and 1146 cmꢁ1 1H NMR (300 MHz, CDCl3)
;
NMR (300 MHz, CDCl3)
d
1.07 (t, 3H, J¼7.1 Hz), 2.47 (s, 3H), 3.87 (s,
d
1.10 (t, 3H, J¼7.1 Hz), 3.94 (s, 6H), 4.23 (q, 2H, J¼7.1 Hz), 6.83 (d,1H,
3H), 3.91 (s, 3H), 4.18 (q, 2H, J¼7.1 Hz), 6.80e6.87 (m, 2H), 6.91 (d,
1H, J¼8.2 Hz), 7.03 (dd, 1H, J¼8.8 and 2.2 Hz), 7.33e7.38 (m, 3H),
7.75 (d, 2H, J¼8.2 Hz), and 8.16 (d, 1H, J¼8.8 Hz); 13C NMR (75 MHz,
J¼8.4 Hz), 7.27e7.36 (m, 2H), 7.48e7.57 (m, 2H), 7.65 (d, 1H,
J¼7.0 Hz), 7.66 (s,1H); 13C NMR (75 MHz, CDCl3)
d 189.1,158.7,154.5,
154.1, 149.3, 142.2, 130.4, 128.3, 126.8, 126.1, 125.6, 124.4, 122.0,
112.4, 110.2, 109.9, 61.8, 56.1, 56.0, and 13.7; HRMS calcd for
[(C20H18O6)þNa]þ: 377.0996. Found: 377.0992.
CDCl3)
d 176.6, 161.5, 155.7, 153.6, 151.4, 149.7, 148.8, 146.1, 131.8,
130.0, 128.4, 128.1, 125.5, 123.0, 122.9, 122.2, 113.0, 112.1, 110.9, 62.6,
55.9 (ꢂ2), 21.8, 13.6; HRMS calcd for [(C27H24O4S)þH]þ: 525.1238
Found: 525.1219.
4.9.12. Diethyl-4-oxo-3-phenyl-4H-chromene-2,7-dicarboxylate (2l),
diethyl-3-benzoylbenzofuran-2,6-dicarboxylate (3l), and diethyl benzo-
furan-2,6-dicarboxylate (9). The diketone 1l (148 mg, 0.39 mmol) and
4.9.9. Ethyl-3-(2-methoxyphenyl)-4-oxo-4H-chromene-2-
carboxylate (2i). The diketone 1i (18 mg, 50
m
mol) and DBU (10
mL,
DBU (82 mL, 0.42 mmol) were used. The reaction mixture was heated
55 mol) were used. The reaction mixture was heated for 3 h. Pu-
m
for 1 h. Purification by preparative thin layer chromatography (SiO2,
20% EtOAc/hexane) provided the title compound 2l (39 mg, 54%
yield) as a colorless solid, compound 3l (9 mg, 12% yield) as a pale
yellow solid, and compound 9 (7 mg, 14% yield) as a colorless solid;
2l: mp 103e104 ꢀC; IR (neat) 2983, 1724, 1653, 1429, 1278, and
rification by preparative thin layer chromatography (SiO2, 25%
EtOAc/hexane) provided the title compound 2i (11 mg, 61% yield) as
a pale yellow oil; 2i: IR (neat) 2926, 1738, 1651, 1464, 1244, and
754 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
1.01 (t, 3H, J¼7.0 Hz), 3.74 (s,
3H), 4.14 (q, 2H, J¼7.0 Hz), 6.95 (d, 1H, J¼8.1 Hz), 7.02 (t, 1H,
J¼7.5 Hz), 7.19 (d, 1H, J¼7.4 Hz), 7.37 (t, 1H, J¼7.9 Hz), 7.44 (t, 1H,
J¼7.5 Hz), 7.59 (d, 1H, J¼8.5 Hz), 7.73 (t, 1H, J¼7.9 Hz), and 8.24 (d,
1203 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
1.01 (t, 3H, J¼7.1 Hz), 1.45 (t,
3H, J¼7.1 Hz), 4.16 (q, 2H, J¼7.1 Hz), 4.46 (q, 2H, J¼7.1 Hz), 7.29e7.32
(m, 2H), 7.41e7.46 (m, 3H), 8.07 (dd, 1H, J¼8.3 and 1.3 Hz), and 8.29 (t,
1H, J¼8.1 Hz); 13C NMR (75 MHz, CDCl3)
d
177.3, 161.6, 156.9, 155.5,
2H, J¼8.3 Hz); 13C NMR (100 MHz, CDCl3)
d 176.9, 164.8, 161.3, 155.0,

S. Bensulong et al. / Tetrahedron 69 (2013) 9335e9348
9347
151.4,135.9,130.9, 129.6, 128.5,128.2, 126.6,126.3, 126.2,125.9, 120.2,
62.6, 61.9, 14.2 and 13.4; HRMS calcd for [(C21H18O6)þNa]þ:
389.0996. Found: 389.1001.
Compound 11r: mp 181e183 ꢀC; 1H NMR (300 MHz, CDCl3)
3.86 (s, 3H), 6.20 (s, 1H), 6.91 (d, 2H, J¼8.2 Hz), and 8.05 (d, 2H,
d
J¼8.2 Hz); 13C NMR (75 MHz, CDCl3)
d 165.0, 163.9, 132.2, 121.4,
Compound 3l: mp 113e115 ꢀC; IR (neat) 2922, 2847, 1670, 1720
113.7, and 55.4.
and 1301 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
1.02 (t, 3H, J¼7.1 Hz),
1.44 (t, 3H, J¼7.1 Hz), 4.18 (q, 2H, J¼7.1 Hz), 4.44 (q, 2H, J¼7.1 Hz),
7.49 (t, 2H, J¼8.0 Hz), 7.64 (d, 2H, J¼8.3 Hz), 7.91 (d, 2H, J¼7.8 Hz),
8.04 (dd, 1H, J¼8.3 and 1.3 Hz), and 8.36 (s, 1H); 13C NMR (100 MHz,
Acknowledgements
This work was supported by Thailand Research Fund Grant
MRG5380136, and in part by Chulabhorn Research Institute, Chu-
labhorn Graduate Institute, and Center of Excellence on Environ-
mental Health and Toxicology.
CDCl3)
d 190.1, 165.8, 158.2, 154.0, 145.0, 137.2, 134.0, 130.6, 130.3,
129.4, 128.7, 125.5, 125.2, 121.9, 114.1, 62.2, 61.5, 14.3, and 14.5;
HRMS calcd for [(C21H18O6)þNa]þ: 389.0996. Found: 389.1001.
Compound 9: mp 76e78 ꢀC; IR (neat) 2982, 2919, 1715, 1291,
1181 and 1016 cmꢁ1 1H NMR (300 MHz, CDCl3)
; d 1.36 (q, 6H,
Supplementary data
J¼6.3 Hz), 4.37 (q, 4H, J¼6.7 Hz), 7.48 (s, 1H), 7.66 (d, 1H, J¼8.2 Hz),
7.94 (d, 1H, J¼8.2 Hz), and 8.21 (s, 1H); 13C NMR (100 MHz, CDCl3)
1H NMR and 13C NMR data. Supplementary data related to this ar-
ticle can be found online at http://dx.doi.org/10.1016/j.tet.2013.07.104.
d
166.1, 159.1, 155.0, 148.1, 130.8, 129.7, 124.7, 122.4, 113.9, 113.2, 61.7,
61.3, and 14.2; HRMS calcd for [(C14H14O5)þNa]þ: 285.0734. Found:
285.0734.
References and notes
4.9.13. Ethyl-3-pivaloylbenzofuran-2-carboxylate (3m). The dike-
tone 1m (41 mg, 0.14 mmol) and DBU (30 mL, 0.15 mmol) were used.
1. Selected examples for benzofuran bioactivities: (a) Abdel-Aziz, H. A.; Mekawey,
A. A. I. Eur. J. Med. Chem. 2009, 44, 4985; (b) Aslam, S. N.; Stevenson, P. C.;
Kokubun, T.; Hall, D. R. Microbiol. Res. 2009, 164, 191; (c) Galal, S. A.; Abd El-All,
A. S.; Abdallah, M. M.; El-Diwani, H. I. Bioorg. Med. Chem. Lett. 2009, 19, 2420;
(d) Dawood, K. M.; Abdel-Gawad, H.; Rageb, E. A.; Ellithey, M.; Mohamed, H. A.
Bioorg. Med. Chem. 2006, 14, 3672; (e) Miert, S. V.; Dyck, S. V.; Schmidt, T. J.;
Brun, R.; Vlietinck, A.; Lemiere, g.; Pieters, L. Bioorg. Med. Chem. 2005, 13, 661;
(f) Li, Y. T.; Yao, C. S.; Bai, J. Y.; Lin, M.; Cheng, G. F. Acta Pharmacol. Sin. 2006, 27,
735; (g) Jiang, X.; Liu, W.; Zhang, W.; Jiang, F.; Gao, Z.; Zhuang, H.; Fu, L. Eur. J.
Med. Chem. 2011, 46, 3526 Selected examples for benzopyran bioactivities: (h)
Gavande, N.; Karim, N.; Johnston, G. A. R.; Hanrahan, J. R.; Chebib, M. Chem-
MedChem 2011, 6, 1340; (i) Raj, T.; Bhatia, R. K.; Sharma, R. K.; Gupta, V.; Sharma,
D.; Ishar, M. P. S. Eur. J. Med. Chem. 2009, 44, 3209; (j) Richardson, T. I.; Norman,
B. H.; Lugar, C. W.; Jones, S. A.; Wang, Y.; Durbin, J. D.; Krishnan, V.; Dodge, J. A.
Bioorg. Med. Chem. Lett. 2007, 17, 3570; (k) Legoabe, L. J.; Petzer, A.; Petzer, J. P.
Bioorg. Chem. 2012, 45, 1; (l) Tahtaoui, C.; Demailly, A.; Guidemann, C.; Joyeux,
C.; Schneider, P. J. Org. Chem. 2010, 75, 3781; (m) Musiliyu, A.; Musa, J. S.;
Cooperwood, M.; Khan, O. F. Curr. Med. Chem. 2008, 15, 2664.
The reaction mixture was heated for 4 h. Purification by preparative
thin layer chromatography (SiO2 30% EtOAc/hexane) provided the
title compound 3m (16 mg, 42% yield) as a pale yellow oil; IR (neat)
2973, 1713, 1696, 1586, 1296, and 1154 cmꢁ1 1H NMR (400 MHz,
;
CDCl3)
(td, 1H, J¼8.0 and 7.3 Hz), 7.49 (m, 2H), and 7.60 (d, 1H, J¼9.2 Hz);
13C NMR (100 MHz, CDCl3)
207.9, 158.8, 154.4, 128.2, 127.7, 126.0,
d
1.32 (s, 9H),1.41 (t, 3H, J¼7.1 Hz), 4.43 (q, 2H, J¼7.1 Hz), 7.33
d
124.2, 122.1, 112.5, 61.9, 45.3, 29.6, 26.8, and 14.2; HRMS calcd for
[(C16H18O4)þH]þ: 275.1239. Found: 275.1277.
4.9.14. Ethyl-3-(3,4-dimethoxybenzoyl)-4,6-dimethoxybenzofuran-
2-carboxylate (3n). The diketone 1n (62 mg, 0.14 mmol) and DBU
(22
m
L, 0.16 mmol) were used. The reaction mixture was heated for
2. (a) Fischer, J.; Savage, G. P.; Coster, M. J. Org. Lett. 2011, 13, 3376; (b) Inoue, M.;
Carson, M. W.; Frontier, A. J.; Danishefsky, S. J. J. Am. Chem. Soc. 2001, 123, 1878;
(c) Ying, K.; Yan, M.; Yuguo, D.; Zhendong, J. Org. Lett. 2003, 5, 4481; (d) Nic-
olaou, K. C.; Pfefferkorn, J. A.; Roecker, A. J.; Cao, G.-Q.; Barluenga, S.; Mitchell,
H. J. J. Am. Chem. Soc. 2000, 122, 9939; (e) Nicolaou, K. C.; Pfefferkorn, J. A.;
Roecker, A. J.; Cao, G.-Q.; Barluenga, S.; Mitchell, H. J. J. Am. Chem. Soc 2000, 122,
9939; (f) Zhang, Y.; Lv, Z.; Zhong, H.; Geng, D.; Zhang, M.; Zhang, T.; Li, Y.; Li, K.
Eur. J. Med. Chem. 2012, 53, 356; (g) Affleck, R. L.; Lillig, J. E. J. Am. Chem. Soc.
2000, 122, 9954.
2 h. Purification by preparative thin layer chromatography (SiO2
25% EtOAc/hexane) provided the title compound 3n (38 mg, 64%
yield) as a pale yellow oil; IR (neat) 2939,1711,1589,1508,1259, and
1151 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
1.10 (t, 3H, J¼7.1 Hz), 3.68 (s,
3H), 3.87 (s, 3H), 3.93 (s, 3H), 3.96 (s, 3H), 4.21 (q, 2H, J¼7.1 Hz), 6.30
(s, 1H), 6.70 (s, 1H), 6.81 (d, 1H, J¼8.4 Hz), 7.30 (d, 1H, J¼8.4 Hz), and
7.66 (s, 1H); 13C NMR (75 MHz, CDCl3)
d 189.7, 162.6, 158.7, 156.8,
3. (a) For review of benzofuran syntheses see: Yeung, K.-S.; Yang, Z.; Peng, X.-S.;
Hou, X.-L. In Progress in Heterocyclic Chemistry; Gribble, G. W., Joule, J. A., Eds.;
Elsevier: Oxford, UK, 2011; Vol. 22, pp 181e216; and previous issues in the
series; (b) For review of benzofuran syntheses see: Hepworth, J. D.; Heron, B. M.
In Progress in Heterocyclic Chemistry; Gribble, G. W., Joule, J. A., Eds.; Elsevier:
Oxford, UK, 2011; Vol. 22, pp 449e490; and previous issues in the series.
4. For recent studies on intramolecular carboneoxygen bond cyclization reactions
of ortho substituted phenols: (a) Dai, W. M.; Lai, K. W. Tetrahedron Lett. 2002, 43,
154.9, 153.7, 149.1, 139.5, 130.5, 126.5, 125.5, 111.1, 110.0, 109.9, 95.6,
87.9, 61.4, 56.1, 56.0, 55.9, 55.8, and 13.9; HRMS calcd for
[(C22H22O8)þNa]þ: 437.1207. Found: 437.1215.
4.9.15. Ethyl-6-nitro benzofuran-2-carboxylate (10). The diketone
1q (50 mg, 0.14 mmol) and DBU (30 mL, 0.15 mmol) were used. The
ꢀ
9377; (b) Eidamshaus, C.; Burch, J. D. Org. Lett. 2008, 10, 4211; (c) Csekei, M.;
ꢀ
Novak, Z.; Kotschy, A. Tetrahedron 2008, 64, 8992; (d) Martinez, C.; Alvarez, R.;
reaction mixture was heated for 1 h. Purification by preparative
thin layer chromatography (SiO2, 10% EtOAc/hexane) provided the
title compound 10 (24 mg, 75% yield) as a pale yellow solid and
5 mg (37%) of benzoic acid (11q). The benzofuran 10 can also be
produced from diketone 1r as following: the diketone 1r (400 mg,
Aurrecoechea, J. M. Org. Lett. 2009, 11, 1083; (e) Liang, Z.; Ma, S.; Yu, J.; Xu, R.
Tetrahedron 2007, 63, 12877; (f) Bernini, R.; Cacchi, S.; Salve, I. D.; Fabrizi, G.
Synthesis 2007, 873; (g) Aponick, A.; Biannic, B.; Jong, M. Chem. Commun. 2010,
6849; (h) Larock, R. C.; Wei, L.; Hightower, T. R. Synlett 1998, 522.
5. (a) Piemontese, L.; Carbonara, G.; Fracchiolla, G.; Laghezza, A.; Tortorella, P.;
Loiodice, F. Heterocycles 2010, 81, 2865; (b) Park, K. K.; Jeong, J. Tetrahedron
2005, 61, 545; (c) Kraus, G. A.; Zhang, N.; Verkade, J.; Nagarajan, M.; Kisanga, P.
Org. Lett. 2000, 2, 2409; (d) Muller, A.; Meszaros, M.; Kormendy, K. J. Org. Chem.
1954, 19, 472; (e) Horaguchi, T.; Tanemura, K.; Suzuki, T. J. Heterocycl. Chem.
1988, 25, 39; (f) Horaguchi, T.; Kobayashi, H.; Miyazawa, K.; Hasegawa, E.;
Shimizu, T. J. Heterocycl. Chem. 1990, 27, 935; (g) Boehm, T. L.; Showalter, H. D.
H. J. Org. Chem. 1996, 61, 6498.
6. (a) Kraus, G. A.; Zhang, N. J. Org. Chem. 2000, 65, 5644; (b) Sharshira, E. M.;
Okamura, M.; Hasegawa, E.; Horaguchi, T. J. Heterocycl. Chem. 1997, 34, 861; (c)
Pappas, S. P.; Pappas, B. C.; Backwell, J. E., Jr. J. Org. Chem. 1967, 32, 3066.
7. (a) Bi, H.-P.; Guo, L.-N.; Gou, F.-R.; Duan, X.-H.; Liu, X.-Y.; Liang, Y.-M. J. Org.
Chem. 2008, 73, 4713; (b) Hu, J.; Wang, X.-C.; Gou, L.-N.; Hu, Y.-Y.; Liu, X.-Y.;
Liang, Y.-M. Catal. Commun. 2010, 11, 346.
1.03 mmol) and DBU (215 mL, 1.14 mmol) were used. The reaction
mixture was heated for 1 h. Purification by preparative thin layer
chromatography (SiO2, 20% EtOAc/hexane) provided the title
compound 10 (194 mg, 80% yield) as a pale yellow solid and 55 mg
(41%) of para methoxybenzoic acid (11r) as brown needles; 10: mp
112e115 ꢀC; IR (neat) 3106, 2987, 1732, 1716, 1516, and 1290 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
J¼7.1 Hz), 7.61 (s, 1H), 7.83 (d, 1H, J¼8.7 Hz), 8.24 (dd, 1H, J¼8.7 and
1.9 Hz), and 8.50 (s, 1H); 13C NMR (75 MHz, CDCl3)
158.6, 154.1,
d
1.46 (t, 3H, J¼7.1 Hz), 4.49 (q, 2H,
d
150.2, 147.1, 132.4, 123.1, 119.2, 112.9, 108.8, 62.2, and 14.2; HRMS
Calcd for [C11H9NO5] : 235.0475. Found: 235.0471.
8. Kanazawa, C.; Goto, K.; Terada, M. Chem. Commun. 2009, 5248.
9. (a) Chen, P.-Y.; Wang, T. P.; Huang, K.-S.; Koa, C.-L.; Tsai, J.-C.; Wang, E.-C. Tet-
rahedron 2011, 67, 9291; (b) Chen, L.-Y.; Li, S.-R.; Chen, P. Y.; Tsai, I.-L.; Hsu, C. L.;
Lin, H. P.; Wang, T. P.; Wang, E.-C. Tetrahedron Lett. 2009, 50, 5748; (c) Li, S.-R.;
Shu, C.-J.; Chen, L.-Y.; Chen, H.-M.; Chen, P. Y.; Wang, E.-C. Tetrahedron 2009, 65,
8702.
Compound 11q: mp 123e125 ꢀC; 1H NMR (300 MHz, CDCl3)
d
6.26 (s, 1H), 7.45 (t, 2H, J¼7.8 Hz), 7.59 (t,1H, J¼7.8 Hz), and 8.11 (d,
2H, J¼7.8 Hz); 13C NMR (75 MHz, CDCl3)
d 133.8, 130.2, and 128.6.
́
́

9348
S. Bensulong et al. / Tetrahedron 69 (2013) 9335e9348
10. Thasana, N.; Prachyawarakorn, V.; Tontoolarug, S.; Ruchirawat, S. Tetrahedron
Lett. 2003, 44, 1019.
11. Tummatorn, J.; Khorphueng, P.; Petsom, A.; Muangsin, N.; Chaichit, N.;
128.9, 128.8, 126.9, 125.8, 122.2, 119.5, 117.6, 82.3, 74.3, 61.9, and 13.8; HRMS
calcd for [(C20H18O6)þH]þ: 355.0890. Found: 355.0890.
19. Excellent performance of DBU in highly polar solvents was also reported in
Kanazawa, C.; Terada, M. Tetrahedron Lett. 2007, 48, 933.
Roengsumran, S. Tetrahedron 2007, 63, 11878.
12. Another approach to compound 2 ring system has been reported using acyla-
tion of ortho hydroxyphenone with ethylchlorooxoacetate followed by in situ
cyclization of the resulting esters in the presence of pyridine: (a) Hauser, F. M.;
Dorsch, W. A. Org. Lett. 2003, 5, 3753; (b) Lee, K. S.; Seo, S. H.; Lee, Y. H.; Kim, H.
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13. (a) Schank, K.; Beck, H.; Himbert, G. Synthesis 1998, 12, 1718; (b) Yusubov, M. S.;
Filimonov, V. D.; Chi, K. W. Russ. Chem. Bull. 2001, 50, 649; (c) Giraud, A.;
Provot, O.; Peyrat, J. F.; Alami, M.; Brion, J. D. Tetrahedron 2006, 62, 7667; (d)
Mousset, C.; Provot, O.; Hamze, A.; Bignon, J.; Brion, J. D.; Alami, M. Tetrahedron
2008, 64, 4287; (e) Che, C.-M.; Yu, W.-Y.; Chan, P.-M.; Cheng, W.-C.; Peng, S.-M.;
Lau, K.-C.; Li, W.-K. J. Am. Chem. Soc. 2000, 122, 11380.
20. Kadesch, R.; Weller, S. W. J. Am. Chem. Soc. 1941, 63, 1310.
21. 37% of 11n and 41% of 11o were isolated.
22. (a) Wangteeraprasert, R.; Likhitwitayawuid, K. Heterocycles 2008, 75, 403; (b)
Ngandeu, F.; Bezabih, M.; Ngamga, D.; Tchinda, A. T.; Ngadjui, B. T.; Abegaz, B. M.;
Dufat, H.; Tillequin, F. Phytochemistry 2008, 69, 258; (c) Lu, H.-Y.; Liang, J.-Y. J. Asian
Nat. Prod. Res. 2009, 11, 58; (d) Ye, H.; Chen, L.; Li, Y.; Peng, A.; Fu, A.; Song, H.;
Tang, M.; Luo, H.; Luo, Y.; Xu, Y.; Shi, J.; Wei, Y. J. Chromatogr. A 2008, 1178, 101; (e)
Silva, B. P.; Bernardo, R. R.; Parente, J. P. Phytochemistry 1995, 49, 1787.
23. (a) Kiran, Y. B.; Konakahara, T.; Sakai, N. Synthesis 2008, 15, 2327; (b) Abe, H.;
Suzuki, H. Bull. Chem. Soc. Jpn. 1999, 72, 787.
24. Carson, M. W.; Giese, M. W.; Coghlan, M. J. Org. Lett. 2008, 10, 2701.
25. (a) Tsou, H. R.; Liu, X.; Birnberg, G.; Kaplan, J.; Otteng, M.; Tran, T.; Kutterer, K.;
Tang, Z.; Suayan, R.; Zask, A.; Ravi, M.; Bretz, A.; Grillo, M.; McGinnis, J. P.;
Rabindran, S. K.; Ayral-Kaloustian, S.; Mansour, T. S. J. Med. Chem. 2009, 52,
2289; (b) Moumne, R.; Lavielle, S.; Karoyan, P. J. Org. Chem. 2006, 71, 3332.
26. Altenburger, J. M.; Fossey, V.; Lassalle, G.; Petit, F.; Vernieres, J. C.; Janiak, P.
Sanofi Aventis December 2009. US 20090318473.
14. Ren, W.; Xia, Y.; Ji, S. J.; Zhang, Y.; Wan, X.; Zhao, J. Org. Lett. 2009, 11, 1841.
15. Zibuck, R.; Seebach, D. Helv. Chim. Acta 1988, 71, 237.
16. Yang, D.; Zhang, C. J. Org. Chem. 2001, 66, 4814.
17. The crude NMR spectrum showed
a mixture of 2-(2-ethoxy-2-oxoethoxy)
benzoic acid 8 and a small amount of corresponding diketone derivative 1p or
1q. However, after column chromatography, the only isolated compound was
27. Magnus, P.; Freund, W. A.; Moorhead, E. J.; Rainey, T. J. Am. Chem. Soc. 2012, 134,
6140.
28. Bachu, P.; Sperry, J.; Brimble, M. A. Tetrahedron 2008, 64, 3343.
29. Hiroya, K.; Suzuki, N.; Yasuhara, A.; Egawa, Y.; Kasano, A.; Sakamoto, T. J. Chem.
Soc., Perkin Trans. 1 2000, 4339.
. IR (neat) 3266, 2929, 1729, 1603, and 1220 cmꢁ1
;
1H NMR
(300 MHz, CDCl3)
d
1.35 (t, 3H, J¼7.1 Hz), 4.35 (q, 2H, J¼7.1 Hz), 4.83 (s, 2H), 6.94
30. Gupton, J. T.; Telang, N.; Banner, E. J.; Kluball, E. J.; Hall, K. E.; Finzel, K. L.; Jia, X.;
Bates, S. R.; Welden, R. S.; Giglio, B. C.; Eaton, J. E.; Barelli, P. J.; Firich, L. T.;
Stafford, J. A.; Coppock, M. B.; Worrall, E. F.; Kanters, R. P. F.; Keertikar, K.;
Osterman, R. Tetrahedron 2010, 66, 9113.
31. Zhao, M.; Kuang, C.; Yang, Q.; Cheng, X. Tetrahedron Lett. 2011, 52, 992.
32. (a) Portscheller, J. L.; Malinakova, H. C. Org. Lett. 2002, 4, 3679; (b) Wu, C.-F.;
Zhao, X.; Lan, W.-X.; Cao, C.; Liu, J.-T.; Jiang, X.-K.; Li, Z.-T. J. Org. Chem. 2012,
77, 4261.
(dd, 1H, J¼8.3 and 0.8 Hz), 7.19 (td, 1H, J¼7.8 and 0.8 Hz), 7.56 (td, 1H, J¼7.8 and
1.8 Hz), and 8.21 (dd, 1H, J¼7.8 and 1.8 Hz); 13C NMR (75 MHz, CDCl3)
d 167.5,
164.9, 156.2, 134.8, 134.2, 123.2, 123.1, 112.8, 66.3, 62.5, and 14.0; HRMS calcd for
[(C11H12O5)þH]þ: 225.0758. Found: 225.0755.
18. Spectroscopic data of II: IR (neat) 3462, 2982, 1740, 1697, 1608, 1462, 1297,
1185 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
1.06 (t, 3H, J¼7 Hz) 1.21 (3H, t, J¼7.
1 Hz), 4.19 (2H, q, J¼7.1 Hz), 4.50 (s), 5.30 (1H,s), 6.97 (1H, dd, J¼8.3, 0.5 Hz), 7.
07 (1H, td, J¼7.6 and 1.0 Hz), 7.35e7.30 (3H,m), 7.55e7.50 (3H,m), and 7.87 (1H,
33. Baker, W.; Chadderton, J.; Harborne, J. B.; Ollis, W. D. J. Chem. Soc. 1953,
1852.
dd, J¼7.8, 1.7 Hz),; 13C NMR (100 MHz, CDCl3)
d 192.0, 168.1, 158.9, 138.3, 136.9,